Array ( [0] => {{short description|Small non-coding ribonucleic acid molecule}} [1] => {{cs1 config|name-list-style=vanc|display-authors=6}} [2] => {{Hatnote|Not to be confused with [[Mitochondrial DNA]] (m(t)DNA); or [[messenger RNA]] (mRNA).}} [3] => {{Use dmy dates|date=September 2019}} [4] => {{DISPLAYTITLE:microRNA}} [5] => [[File:MiRNA.svg|thumb|400px|Pre-miRNA instead of Pri-miRNA in the first point of mechanism. Diagram of microRNA (miRNA) action with [[mRNA]]]] [6] => [[File:Examples of microRNA stem-loops.jpg|thumb|400px|Examples of miRNA stem-loops, with the mature miRNAs shown in red]] [7] => '''MicroRNA''' ('''miRNA''') are small, single-stranded, [[non-coding RNA]] molecules containing 21 to 23 [[nucleotide]]s.{{cite journal | vauthors = Bartel DP | title = Metazoan MicroRNAs | journal = Cell | volume = 173 | issue = 1 | pages = 20–51 | date = March 2018 | pmid = 29570994 | pmc = 6091663 | doi = 10.1016/j.cell.2018.03.006 }} Found in plants, animals and some viruses, miRNAs are involved in [[RNA silencing]] and post-transcriptional [[regulation of gene expression]].{{cite journal | vauthors = Bartel DP | title = MicroRNAs: genomics, biogenesis, mechanism, and function | journal = Cell | volume = 116 | issue = 2 | pages = 281–297 | date = January 2004 | pmid = 14744438 | doi = 10.1016/S0092-8674(04)00045-5 | doi-access = free }}{{cite journal|vauthors=Qureshi A, Thakur N, Monga I, Thakur A, Kumar M|date=1 January 2014|title=VIRmiRNA: a comprehensive resource for experimentally validated viral miRNAs and their targets|journal=Database|volume=2014|pages=bau103|doi=10.1093/database/bau103|pmc=4224276|pmid=25380780}} miRNAs [[base-pair]] to complementary sequences in [[mRNA]] molecules,{{cite journal | vauthors = Bartel DP | title = MicroRNAs: target recognition and regulatory functions | journal = Cell | volume = 136 | issue = 2 | pages = 215–33 | date = January 2009 | pmid = 19167326 | pmc = 3794896 | doi = 10.1016/j.cell.2009.01.002 }} then [[Gene silencing|silence]] said [[mRNA]] molecules by one or more of the following processes:{{cite journal | vauthors = Jonas S, Izaurralde E | title = Towards a molecular understanding of microRNA-mediated gene silencing | journal = Nature Reviews. Genetics | volume = 16 | issue = 7 | pages = 421–433 | date = July 2015 | pmid = 26077373 | doi = 10.1038/nrg3965 | s2cid = 24892348 }} [8] => [9] => # Cleavage of the mRNA strand into two pieces, [10] => # Destabilization of the mRNA by shortening its [[polyadenylation|poly(A) tail]], or [11] => # Reducing [[translation (biology)|translation]] of the mRNA into proteins. [12] => [13] => In cells of humans and other animals, miRNAs primarily act by destabilizing the mRNA.{{cite journal | vauthors = Jonas S, Izaurralde E | title = Towards a molecular understanding of microRNA-mediated gene silencing | journal = Nature Reviews. Genetics | volume = 16 | issue = 7 | pages = 421–433 | date = July 2015 | pmid = 26077373 | doi = 10.1038/nrg3965 | s2cid = 24892348 }}{{cite journal | vauthors = Guo H, Ingolia NT, Weissman JS, Bartel DP | title = Mammalian microRNAs predominantly act to decrease target mRNA levels | journal = Nature | volume = 466 | issue = 7308 | pages = 835–840 | date = August 2010 | pmid = 20703300 | pmc = 2990499 | doi = 10.1038/nature09267 | hdl-access = free | bibcode = 2010Natur.466..835G | hdl = 1721.1/72447 }} [14] => [15] => miRNAs resemble the [[small interfering RNA|small interfering RNAs (siRNAs)]] of the [[RNA interference|RNA interference (RNAi)]] pathway, except miRNAs derive from regions of RNA transcripts that fold back on themselves to form short hairpins, whereas siRNAs derive from longer regions of [[double-stranded RNA]]. The [[human genome]] may encode over 1900 miRNAs,[http://www.mirbase.org/cgi-bin/mirna_summary.pl?org=hsa ''Homo sapiens'' miRNAs in the miRBase] at [[Manchester University]]{{cite journal | vauthors = Alles J, Fehlmann T, Fischer U, Backes C, Galata V, Minet M, Hart M, Abu-Halima M, Grässer FA, Lenhof HP, Keller A, Meese E | title = An estimate of the total number of true human miRNAs | journal = Nucleic Acids Research | volume = 47 | issue = 7 | pages = 3353–3364 | date = April 2019 | pmid = 30820533 | pmc = 6468295 | doi = 10.1093/nar/gkz097 }} However, only about 500 human miRNAs represent bona fide miRNAs in the manually curated miRNA gene database [[MirGeneDB]].{{cite journal | vauthors = Fromm B, Domanska D, Høye E, Ovchinnikov V, Kang W, Aparicio-Puerta E, Johansen M, Flatmark K, Mathelier A, Hovig E, Hackenberg M, Friedländer MR, Peterson KJ | title = MirGeneDB 2.0: the metazoan microRNA complement | journal = Nucleic Acids Research | volume = 48 | issue = D1 | pages = D132–D141 | date = January 2020 | pmid = 31598695 | pmc = 6943042 | doi = 10.1093/nar/gkz885 }} [16] => [17] => miRNAs are abundant in many mammalian cell types{{cite journal | vauthors = Lim LP, Lau NC, Weinstein EG, Abdelhakim A, Yekta S, Rhoades MW, Burge CB, Bartel DP | title = The microRNAs of Caenorhabditis elegans | journal = Genes & Development | volume = 17 | issue = 8 | pages = 991–1008 | date = April 2003 | pmid = 12672692 | pmc = 196042 | doi = 10.1101/gad.1074403 }}{{cite journal | vauthors = Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T | title = Identification of tissue-specific microRNAs from mouse | journal = Current Biology | volume = 12 | issue = 9 | pages = 735–9 | date = April 2002 | pmid = 12007417 | doi = 10.1016/S0960-9822(02)00809-6 | doi-access = free | bibcode = 2002CBio...12..735L }} miRNAs appear to target about 60% of the genes of humans and other mammals.{{cite journal | vauthors = Lewis BP, Burge CB, Bartel DP | title = Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets | journal = Cell | volume = 120 | issue = 1 | pages = 15–20 | date = January 2005 | pmid = 15652477 | doi = 10.1016/j.cell.2004.12.035 | doi-access = free }}{{cite journal | vauthors = Friedman RC, Farh KK, Burge CB, Bartel DP | title = Most mammalian mRNAs are conserved targets of microRNAs | journal = Genome Research | volume = 19 | issue = 1 | pages = 92–105 | date = January 2009 | pmid = 18955434 | pmc = 2612969 | doi = 10.1101/gr.082701.108 }} Many miRNAs are evolutionarily conserved, which implies that they have important biological functions.{{cite journal | vauthors = Fromm B, Billipp T, Peck LE, Johansen M, Tarver JE, King BL, Newcomb JM, Sempere LF, Flatmark K, Hovig E, Peterson KJ | title = A Uniform System for the Annotation of Vertebrate microRNA Genes and the Evolution of the Human microRNAome | journal = Annual Review of Genetics | volume = 49 | pages = 213–42 | date = 2015 | pmid = 26473382 | pmc = 4743252 | doi = 10.1146/annurev-genet-120213-092023 }} For example, 90 families of miRNAs have been conserved since at least the common ancestor of mammals and fish, and most of these conserved miRNAs have important functions, as shown by studies in which genes for one or more members of a family have been knocked out in mice. [18] => [19] => {{toclimit|3}} [20] => [21] => == History == [22] => [23] => The first miRNA was discovered in the early 1990s.{{cite journal | vauthors = Lee RC, Feinbaum RL, Ambros V | title = The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 | journal = Cell | volume = 75 | issue = 5 | pages = 843–54 | date = December 1993 | pmid = 8252621 | doi = 10.1016/0092-8674(93)90529-Y | doi-access = free }} However, miRNAs were not recognized as a distinct class of biological regulators until the early 2000s.{{cite journal | vauthors = Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, Horvitz HR, Ruvkun G | title = The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans | journal = Nature | volume = 403 | issue = 6772 | pages = 901–6 | date = February 2000 | pmid = 10706289 | doi = 10.1038/35002607 | bibcode = 2000Natur.403..901R | s2cid = 4384503 }}{{cite journal | vauthors = Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B, Hayward DC, Ball EE, Degnan B, Müller P, Spring J, Srinivasan A, Fishman M, Finnerty J, Corbo J, Levine M, Leahy P, Davidson E, Ruvkun G | title = Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA | journal = Nature | volume = 408 | issue = 6808 | pages = 86–9 | date = November 2000 | pmid = 11081512 | doi = 10.1038/35040556 | bibcode = 2000Natur.408...86P | s2cid = 4401732 }}{{cite journal | vauthors = Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T | title = Identification of novel genes coding for small expressed RNAs | journal = Science | volume = 294 | issue = 5543 | pages = 853–8 | date = October 2001 | pmid = 11679670 | doi = 10.1126/science.1064921 | bibcode = 2001Sci...294..853L | hdl = 11858/00-001M-0000-0012-F65F-2 | s2cid = 18101169 | hdl-access = free }}{{cite journal | vauthors = Lau NC, Lim LP, Weinstein EG, Bartel DP | title = An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans | journal = Science | volume = 294 | issue = 5543 | pages = 858–62 | date = October 2001 | pmid = 11679671 | doi = 10.1126/science.1065062 | bibcode = 2001Sci...294..858L | s2cid = 43262684 }}{{cite journal | vauthors = Lee RC, Ambros V | title = An extensive class of small RNAs in Caenorhabditis elegans | journal = Science | volume = 294 | issue = 5543 | pages = 862–4 | date = October 2001 | pmid = 11679672 | doi = 10.1126/science.1065329 | bibcode = 2001Sci...294..862L | s2cid = 33480585 }} miRNA research revealed different sets of miRNAs expressed in different cell types and [[Tissue (biology)|tissues]]{{cite journal | vauthors = Wienholds E, Kloosterman WP, Miska E, Alvarez-Saavedra E, Berezikov E, de Bruijn E, Horvitz HR, Kauppinen S, Plasterk RH | title = MicroRNA expression in zebrafish embryonic development | journal = Science | volume = 309 | issue = 5732 | pages = 310–1 | date = July 2005 | pmid = 15919954 | doi = 10.1126/science.1114519 | bibcode = 2005Sci...309..310W | s2cid = 38939571 }} and multiple roles for miRNAs in plant and animal development and in many other biological processes.{{cite journal | vauthors = Brennecke J, Hipfner DR, Stark A, Russell RB, Cohen SM | title = bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila | journal = Cell | volume = 113 | issue = 1 | pages = 25–36 | date = April 2003 | pmid = 12679032 | doi = 10.1016/S0092-8674(03)00231-9 | doi-access = free }}{{cite journal | vauthors = Cuellar TL, McManus MT | title = MicroRNAs and endocrine biology | journal = The Journal of Endocrinology | volume = 187 | issue = 3 | pages = 327–32 | date = December 2005 | pmid = 16423811 | doi = 10.1677/joe.1.06426 | doi-access = free }}{{cite journal | vauthors = Poy MN, Eliasson L, Krutzfeldt J, Kuwajima S, Ma X, Macdonald PE, Pfeffer S, Tuschl T, Rajewsky N, Rorsman P, Stoffel M | title = A pancreatic islet-specific microRNA regulates insulin secretion | journal = Nature | volume = 432 | issue = 7014 | pages = 226–30 | date = November 2004 | pmid = 15538371 | doi = 10.1038/nature03076 | bibcode = 2004Natur.432..226P | s2cid = 4415988 }}{{cite journal | vauthors = Chen CZ, Li L, Lodish HF, Bartel DP | title = MicroRNAs modulate hematopoietic lineage differentiation | journal = Science | volume = 303 | issue = 5654 | pages = 83–6 | date = January 2004 | pmid = 14657504 | doi = 10.1126/science.1091903 | bibcode = 2004Sci...303...83C | hdl = 1721.1/7483 | s2cid = 7044929 | hdl-access = free }}{{cite journal | vauthors = Wilfred BR, Wang WX, Nelson PT | title = Energizing miRNA research: a review of the role of miRNAs in lipid metabolism, with a prediction that miR-103/107 regulates human metabolic pathways | journal = Molecular Genetics and Metabolism | volume = 91 | issue = 3 | pages = 209–17 | date = July 2007 | pmid = 17521938 | pmc = 1978064 | doi = 10.1016/j.ymgme.2007.03.011 }}{{cite journal | vauthors = Harfe BD, McManus MT, Mansfield JH, Hornstein E, Tabin CJ | title = The RNaseIII enzyme Dicer is required for morphogenesis but not patterning of the vertebrate limb | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 31 | pages = 10898–903 | date = August 2005 | pmid = 16040801 | pmc = 1182454 | doi = 10.1073/pnas.0504834102 | bibcode = 2005PNAS..10210898H | doi-access = free }} Aberrant miRNA expression are implicated in disease states. MiRNA-based therapies are under investigation.{{cite journal | vauthors = Trang P, Weidhaas JB, Slack FJ | title = MicroRNAs as potential cancer therapeutics | journal = Oncogene | volume = 27 | issue = Suppl 2 | pages = S52–7 | date = December 2008 | pmid = 19956180 | doi = 10.1038/onc.2009.353 | pmc = 10033140 | doi-access = free }}{{cite journal | vauthors = Li C, Feng Y, Coukos G, Zhang L | title = Therapeutic microRNA strategies in human cancer | journal = The AAPS Journal | volume = 11 | issue = 4 | pages = 747–57 | date = December 2009 | pmid = 19876744 | pmc = 2782079 | doi = 10.1208/s12248-009-9145-9 }}{{cite journal | vauthors = Fasanaro P, Greco S, Ivan M, Capogrossi MC, Martelli F | title = microRNA: emerging therapeutic targets in acute ischemic diseases | journal = Pharmacology & Therapeutics | volume = 125 | issue = 1 | pages = 92–104 | date = January 2010 | pmid = 19896977 | doi = 10.1016/j.pharmthera.2009.10.003 }}{{cite journal | vauthors = Hydbring P, Badalian-Very G | title = Clinical applications of microRNAs | journal = F1000Research | volume = 2 | pages = 136 | date = August 2013 | pmid = 24627783 | pmc = 3917658 | doi = 10.12688/f1000research.2-136.v2 | doi-access = free }} [24] => [25] => The first miRNA was discovered in 1993 by a group led by [[Victor Ambros|Ambros]] and including Lee and Feinbaum. However, additional insight into its mode of action required simultaneously published work by [[Gary Ruvkun|Ruvkun]]'s team, including Wightman and Ha.{{cite journal | vauthors = Wightman B, Ha I, Ruvkun G | title = Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans | journal = Cell | volume = 75 | issue = 5 | pages = 855–62 | date = December 1993 | pmid = 8252622 | doi = 10.1016/0092-8674(93)90530-4 | doi-access = free }} These groups published back-to-back papers on the ''[[lin-4 microRNA precursor|lin-4]]'' gene, which was known to control the timing of ''[[Caenorhabditis elegans|C. elegans]]'' larval development by repressing the ''lin-14'' gene. When Lee et al. isolated the ''lin-4'' miRNA, they found that instead of producing an mRNA encoding a protein, it produced short [[non-coding RNA]]s, one of which was a ~22-nucleotide RNA that contained sequences partially complementary to multiple sequences in the [[3' UTR]] of the ''lin-14'' mRNA. This complementarity was proposed to inhibit the translation of the ''lin-14'' mRNA into the LIN-14 protein. At the time, the ''lin-4'' small RNA was thought to be a [[nematode]] idiosyncrasy. [26] => [27] => In 2000, a second small RNA was characterized: ''[[let-7 microRNA precursor|let-7]]'' RNA, which represses ''lin-41'' to promote a later developmental transition in ''C. elegans''. The ''let-7'' RNA was found to be conserved in many species, leading to the suggestion that ''let-7'' RNA and additional "small temporal RNAs" might regulate the timing of development in diverse animals, including humans. [28] => [29] => A year later, the ''lin-4'' and ''let-7'' RNAs were found to be part of a large class of small RNAs present in ''C. elegans'', ''[[Drosophila]]'' and human cells. The many RNAs of this class resembled the ''lin-4'' and ''let-7'' RNAs, except their expression patterns were usually inconsistent with a role in regulating the timing of development. This suggested that most might function in other types of regulatory pathways. At this point, researchers started using the term "microRNA" to refer to this class of small regulatory RNAs. [30] => [31] => The first human disease associated with deregulation of miRNAs was [[B-cell chronic lymphocytic leukemia|chronic lymphocytic leukemia]]. In this disorder, the miRNAs have a dual role working as both tumor suppressors and [[Oncogene|oncogenes.]]{{cite book | vauthors = Giza DE, Calin GA | title = MicroRNA: Cancer | chapter = MicroRNA and Chronic Lymphocytic Leukemia | series = Advances in Experimental Medicine and Biology | volume = 889 | pages = 23–40 | date = 2015 | pmid = 26658994 | doi = 10.1007/978-3-319-23730-5_2 | isbn = 978-3-319-23729-9 }} [32] => [33] => ==Nomenclature== [34] => Under a standard nomenclature system, names are assigned to experimentally confirmed miRNAs before publication.{{cite journal | vauthors = Ambros V, Bartel B, Bartel DP, Burge CB, Carrington JC, Chen X, Dreyfuss G, Eddy SR, Griffiths-Jones S, Marshall M, Matzke M, Ruvkun G, Tuschl T | title = A uniform system for microRNA annotation | journal = RNA | volume = 9 | issue = 3 | pages = 277–9 | date = March 2003 | pmid = 12592000 | pmc = 1370393 | doi = 10.1261/rna.2183803 }}{{cite journal | vauthors = Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ | title = miRBase: microRNA sequences, targets and gene nomenclature | journal = Nucleic Acids Research | volume = 34 | issue = Database issue | pages = D140–4 | date = January 2006 | pmid = 16381832 | pmc = 1347474 | doi = 10.1093/nar/gkj112 }} The prefix "miR" is followed by a dash and a number, the latter often indicating order of naming. For example, miR-124 was named and likely discovered prior to miR-456. A capitalized "miR-" refers to the mature form of the miRNA, while the uncapitalized "mir-" refers to the pre-miRNA and the {{Not a typo|pri}}-miRNA.{{cite journal | vauthors = Wright MW, Bruford EA | title = Naming 'junk': human non-protein coding RNA (ncRNA) gene nomenclature | journal = Human Genomics | volume = 5 | issue = 2 | pages = 90–8 | date = January 2011 | pmid = 21296742 | pmc = 3051107 | doi = 10.1186/1479-7364-5-2-90 | doi-access = free }} The genes encoding miRNAs are also named using the same three-letter prefix according to the conventions of the organism gene nomenclature. For examples, the official miRNAs gene names in some organisms are "''mir-1'' in ''C. elegans'' and ''Drosophila,'' ''Mir1'' in ''Rattus norvegicus'' and ''MIR25'' in human. [35] => [36] => miRNAs with nearly identical sequences except for one or two nucleotides are annotated with an additional lower case letter. For example, miR-124a is closely related to miR-124b. For example: [37] => [38] => : {{mono|hsa-miR-181a}}: {{DNA sequence|aacauucaACgcugucggugAgu}} [39] => : {{mono|hsa-miR-181b}}: {{DNA sequence|aacauucaUUgcugucggugGgu}} [40] => [41] => Pre-miRNAs, {{Not a typo|pri}}-miRNAs and genes that lead to 100% identical mature miRNAs but that are located at different places in the genome are indicated with an additional dash-number suffix. For example, the pre-miRNAs {{Not a typo|hsa}}-mir-194-1 and {{Not a typo|hsa}}-mir-194-2 lead to an identical mature miRNA ({{Not a typo|hsa}}-miR-194) but are from genes located in different genome regions. [42] => [43] => Species of origin is designated with a three-letter prefix, e.g., {{Not a typo|hsa}}-miR-124 is a human (''Homo sapiens'') miRNA and oar-miR-124 is a sheep (''Ovis aries'') miRNA. Other common prefixes include "v" for viral (miRNA encoded by a viral genome) and "d" for ''Drosophila'' miRNA (a fruit fly commonly studied in genetic research). [44] => [45] => When two mature microRNAs originate from opposite arms of the same pre-miRNA and are found in roughly similar amounts, they are denoted with a -3p or -5p suffix. (In the past, this distinction was also made with "s" ([[antisense|sense]]) and "as" (antisense)). However, the mature microRNA found from one arm of the hairpin is usually much more abundant than that found from the other arm, in which case, an asterisk following the name indicates the mature species found at low levels from the opposite arm of a hairpin. For example, miR-124 and miR-124* share a pre-miRNA hairpin, but much more miR-124 is found in the cell. [46] => [47] => == Targets == [48] => Plant miRNAs usually have near-perfect pairing with their mRNA targets, which induces gene repression through cleavage of the target transcripts.{{cite journal | vauthors = Jones-Rhoades MW, Bartel DP, Bartel B | title = MicroRNAS and their regulatory roles in plants | journal = Annual Review of Plant Biology | volume = 57 | pages = 19–53 | date = 2006 | pmid = 16669754 | doi = 10.1146/annurev.arplant.57.032905.105218 }}{{cite journal |vauthors=Hunt M, Banerjee S, Surana P, Liu M, Fuerst G, Mathioni S, Meyers BC, Nettleton D, Wise RP |title=Small RNA discovery in the interaction between barley and the powdery mildew pathogen |journal=BMC Genomics |volume=20 |pages=19–53 |date=2019 |issue=1 |doi=10.1186/s12864-019-5947-z |pmid=31345162 |pmc=6657096 |doi-access=free }} In contrast, animal miRNAs are able to recognize their target mRNAs by using as few as 6–8 nucleotides (the seed region) at the 5' end of the miRNA,{{cite journal | vauthors = Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB | title = Prediction of mammalian microRNA targets | journal = Cell | volume = 115 | issue = 7 | pages = 787–98 | date = December 2003 | pmid = 14697198 | doi = 10.1016/S0092-8674(03)01018-3 | doi-access = free }}{{cite journal | vauthors = Ellwanger DC, Büttner FA, Mewes HW, Stümpflen V | title = The sufficient minimal set of miRNA seed types | journal = Bioinformatics | volume = 27 | issue = 10 | pages = 1346–50 | date = May 2011 | pmid = 21441577 | pmc = 3087955 | doi = 10.1093/bioinformatics/btr149 }} which is not enough pairing to induce cleavage of the target mRNAs. Combinatorial regulation is a feature of miRNA regulation in animals.{{cite journal | vauthors = Rajewsky N | title = microRNA target predictions in animals | journal = Nature Genetics | volume = 38 | issue = 6s | pages = S8–13 | date = June 2006 | pmid = 16736023 | doi = 10.1038/ng1798 | s2cid = 23496396 }} A given miRNA may have hundreds of different mRNA targets, and a given target might be regulated by multiple miRNAs.{{cite journal | vauthors = Krek A, Grün D, Poy MN, Wolf R, Rosenberg L, Epstein EJ, MacMenamin P, da Piedade I, Gunsalus KC, Stoffel M, Rajewsky N | title = Combinatorial microRNA target predictions | journal = Nature Genetics | volume = 37 | issue = 5 | pages = 495–500 | date = May 2005 | pmid = 15806104 | doi = 10.1038/ng1536 | s2cid = 22672750 }} [49] => [50] => Estimates of the average number of unique messenger RNAs that are targets for repression by a typical miRNA vary, depending on the estimation method,{{cite journal | vauthors = Thomson DW, Bracken CP, Goodall GJ | title = Experimental strategies for microRNA target identification | journal = Nucleic Acids Research | volume = 39 | issue = 16 | pages = 6845–53 | date = September 2011 | pmid = 21652644 | pmc = 3167600 | doi = 10.1093/nar/gkr330 }} but multiple approaches show that mammalian miRNAs can have many unique targets. For example, an analysis of the miRNAs highly conserved in vertebrates shows that each has, on average, roughly 400 conserved targets. Likewise, experiments show that a single miRNA species can reduce the stability of hundreds of unique messenger RNAs.{{cite journal | vauthors = Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP, Linsley PS, Johnson JM | title = Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs | journal = Nature | volume = 433 | issue = 7027 | pages = 769–73 | date = February 2005 | pmid = 15685193 | doi = 10.1038/nature03315 | bibcode = 2005Natur.433..769L | s2cid = 4430576 }} Other experiments show that a single miRNA species may repress the production of hundreds of proteins, but that this repression often is relatively mild (much less than 2-fold).{{cite journal | vauthors = Selbach M, Schwanhäusser B, Thierfelder N, Fang Z, Khanin R, Rajewsky N | title = Widespread changes in protein synthesis induced by microRNAs | journal = Nature | volume = 455 | issue = 7209 | pages = 58–63 | date = September 2008 | pmid = 18668040 | doi = 10.1038/nature07228 | bibcode = 2008Natur.455...58S | s2cid = 4429008 }}{{cite journal | vauthors = Baek D, Villén J, Shin C, Camargo FD, Gygi SP, Bartel DP | title = The impact of microRNAs on protein output | journal = Nature | volume = 455 | issue = 7209 | pages = 64–71 | date = September 2008 | pmid = 18668037 | pmc = 2745094 | doi = 10.1038/nature07242 | doi-broken-date = 26 April 2024 | bibcode = 2008Natur.455...64B }} [51] => [52] => ==Biogenesis== [53] => [[File:MiRNA-biogenesis.jpg|thumb|400px]] [54] => As many as 40% of miRNA genes may lie in the [[intron]]s or even [[exon]]s of other genes.{{cite journal | vauthors = Rodriguez A, Griffiths-Jones S, Ashurst JL, Bradley A | title = Identification of mammalian microRNA host genes and transcription units | journal = Genome Research | volume = 14 | issue = 10A | pages = 1902–10 | date = October 2004 | pmid = 15364901 | pmc = 524413 | doi = 10.1101/gr.2722704 }} These are usually, though not exclusively, found in a sense orientation,{{cite journal | vauthors = Weber MJ | title = New human and mouse microRNA genes found by homology search | journal = The FEBS Journal | volume = 272 | issue = 1 | pages = 59–73 | date = January 2005 | pmid = 15634332 | doi = 10.1111/j.1432-1033.2004.04389.x | s2cid = 32923462 | doi-access = free }} and thus usually are regulated together with their host genes.{{cite journal | vauthors = Kim YK, Kim VN | title = Processing of intronic microRNAs | journal = The EMBO Journal | volume = 26 | issue = 3 | pages = 775–83 | date = February 2007 | pmid = 17255951 | pmc = 1794378 | doi = 10.1038/sj.emboj.7601512 }}{{cite journal | vauthors = Baskerville S, Bartel DP | title = Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes | journal = RNA | volume = 11 | issue = 3 | pages = 241–7 | date = March 2005 | pmid = 15701730 | pmc = 1370713 | doi = 10.1261/rna.7240905 }} [55] => [56] => The DNA template is not the final word on mature miRNA production: 6% of human miRNAs show RNA editing ([[Isomir|IsomiRs]]), the site-specific modification of RNA sequences to yield products different from those encoded by their DNA. This increases the diversity and scope of miRNA action beyond that implicated from the genome alone. [57] => [58] => ===Transcription=== [59] => miRNA genes are usually transcribed by [[RNA polymerase II]] (Pol II).{{cite journal | vauthors = Lee Y, Kim M, Han J, Yeom KH, Lee S, Baek SH, Kim VN | title = MicroRNA genes are transcribed by RNA polymerase II | journal = The EMBO Journal | volume = 23 | issue = 20 | pages = 4051–60 | date = October 2004 | pmid = 15372072 | pmc = 524334 | doi = 10.1038/sj.emboj.7600385 }}{{cite journal | vauthors = Zhou X, Ruan J, Wang G, Zhang W | title = Characterization and identification of microRNA core promoters in four model species | journal = PLOS Computational Biology | volume = 3 | issue = 3 | pages = e37 | date = March 2007 | pmid = 17352530 | pmc = 1817659 | doi = 10.1371/journal.pcbi.0030037 | bibcode = 2007PLSCB...3...37Z | doi-access = free }} The polymerase often binds to a promoter found near the DNA sequence, encoding what will become the hairpin loop of the pre-miRNA. The resulting transcript is [[5' cap|capped]] with a specially modified nucleotide at the 5' end, [[Polyadenylation|polyadenylated]] with multiple [[Adenosine monophosphate|adenosines]] (a poly(A) tail),{{cite journal | vauthors = Cai X, Hagedorn CH, Cullen BR | title = Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs | journal = RNA | volume = 10 | issue = 12 | pages = 1957–66 | date = December 2004 | pmid = 15525708 | pmc = 1370684 | doi = 10.1261/rna.7135204 }} and [[RNA splicing|spliced]]. Animal miRNAs are initially transcribed as part of one arm of an ~80 nucleotide RNA [[stem-loop]] that in turn forms part of a several hundred nucleotide-long miRNA precursor termed a pri-miRNA. When a stem-loop precursor is found in the 3' UTR, a transcript may serve as a pri-miRNA and a mRNA. [[RNA polymerase III]] (Pol III) transcribes some miRNAs, especially those with upstream [[Alu sequence]]s, [[transfer RNA]]s (tRNAs), and [[mammalian wide interspersed repeat]] (MWIR) promoter units.{{cite journal | vauthors = Faller M, Guo F | title = MicroRNA biogenesis: there's more than one way to skin a cat | journal = Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms | volume = 1779 | issue = 11 | pages = 663–7 | date = November 2008 | pmid = 18778799 | pmc = 2633599 | doi = 10.1016/j.bbagrm.2008.08.005 }} [60] => [61] => ===Nuclear processing=== [62] => [[File:5b16 drosha dgcr8.png|thumb|right|A [[X-ray crystallography|crystal structure]] of the human [[Drosha]] protein in complex with the [[C-terminal]] [[alpha helix|helices]] of two [[DGCR8]] molecules (green). Drosha consists of two [[ribonuclease III]] domains (blue and orange); a double-stranded RNA binding domain (yellow); and a connector/platform domain (gray) containing two bound [[zinc]] ion (spheres). From {{PDB|5B16}}.]] [63] => A single pri-miRNA may contain from one to six miRNA precursors. These hairpin loop structures are composed of about 70 nucleotides each. Each hairpin is flanked by sequences necessary for efficient processing. [64] => [65] => The double-stranded RNA (dsRNA) structure of the hairpins in a pri-miRNA is recognized by a nuclear protein known as [[Pasha (protein)|DiGeorge Syndrome Critical Region 8]] (DGCR8 or "Pasha" in invertebrates), named for its association with [[DiGeorge Syndrome]]. DGCR8 associates with the enzyme [[Drosha]], a protein that cuts RNA, to form the [[Microprocessor complex]].{{cite journal | vauthors = Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Rådmark O, Kim S, Kim VN | title = The nuclear RNase III Drosha initiates microRNA processing | journal = Nature | volume = 425 | issue = 6956 | pages = 415–9 | date = September 2003 | pmid = 14508493 | doi = 10.1038/nature01957 | bibcode = 2003Natur.425..415L | s2cid = 4421030 }}{{Cite book | vauthors = Gregory RI, Chendrimada TP, Shiekhattar R | title = MicroRNA Protocols | chapter = MicroRNA biogenesis: isolation and characterization of the microprocessor complex | series = Methods in Molecular Biology | volume = 342 | pages = 33–47 | year = 2006 | pmid = 16957365 | doi = 10.1385/1-59745-123-1:33 | isbn = 978-1-59745-123-9 }} In this complex, DGCR8 orients the catalytic RNase III domain of Drosha to liberate hairpins from pri-miRNAs by cleaving RNA about eleven nucleotides from the hairpin base (one helical dsRNA turn into the stem).{{cite journal | vauthors = Han J, Lee Y, Yeom KH, Kim YK, Jin H, Kim VN | title = The Drosha-DGCR8 complex in primary microRNA processing | journal = Genes & Development | volume = 18 | issue = 24 | pages = 3016–27 | date = December 2004 | pmid = 15574589 | pmc = 535913 | doi = 10.1101/gad.1262504 }}{{cite journal | vauthors = Han J, Lee Y, Yeom KH, Nam JW, Heo I, Rhee JK, Sohn SY, Cho Y, Zhang BT, Kim VN | title = Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex | journal = Cell | volume = 125 | issue = 5 | pages = 887–901 | date = June 2006 | pmid = 16751099 | doi = 10.1016/j.cell.2006.03.043 | doi-access = free }} The product resulting has a two-nucleotide overhang at its 3' end; it has 3' hydroxyl and 5' phosphate groups. It is often termed as a pre-miRNA (precursor-miRNA). Sequence motifs downstream of the pre-miRNA that are important for efficient processing have been identified.{{cite journal | vauthors = Conrad T, Marsico A, Gehre M, Orom UA | title = Microprocessor activity controls differential miRNA biogenesis in Vivo | journal = Cell Reports | volume = 9 | issue = 2 | pages = 542–54 | date = October 2014 | pmid = 25310978 | doi = 10.1016/j.celrep.2014.09.007 | doi-access = free }}{{cite journal | vauthors = Auyeung VC, Ulitsky I, McGeary SE, Bartel DP | title = Beyond secondary structure: primary-sequence determinants license pri-miRNA hairpins for processing | journal = Cell | volume = 152 | issue = 4 | pages = 844–58 | date = February 2013 | pmid = 23415231 | pmc = 3707628 | doi = 10.1016/j.cell.2013.01.031 }}{{cite journal | vauthors = Ali PS, Ghoshdastider U, Hoffmann J, Brutschy B, Filipek S | title = Recognition of the let-7g miRNA precursor by human Lin28B | journal = FEBS Letters | volume = 586 | issue = 22 | pages = 3986–90 | date = November 2012 | pmid = 23063642 | doi = 10.1016/j.febslet.2012.09.034 | s2cid = 28899778 | doi-access = free }} [66] => [67] => Pre-miRNAs that are [[RNA splicing|spliced]] directly out of introns, bypassing the Microprocessor complex, are known as "[[mirtrons]]."{{cite journal | vauthors = Ruby JG, Jan CH, Bartel DP | title = Intronic microRNA precursors that bypass Drosha processing | journal = Nature | volume = 448 | issue = 7149 | pages = 83–86 | date = July 2007 | pmid = 17589500 | pmc = 2475599 | doi = 10.1038/nature05983 | bibcode = 2007Natur.448...83R }} Mirtrons have been found in ''Drosophila'', ''C. elegans'', and mammals.{{cite journal | vauthors = Ruby JG, Jan CH, Bartel DP | title = Intronic microRNA precursors that bypass Drosha processing | journal = Nature | volume = 448 | issue = 7149 | pages = 83–86 | date = July 2007 | pmid = 17589500 | pmc = 2475599 | doi = 10.1038/nature05983 | bibcode = 2007Natur.448...83R }}{{cite journal | vauthors = Berezikov E, Chung WJ, Willis J, Cuppen E, Lai EC | title = Mammalian mirtron genes | journal = Molecular Cell | volume = 28 | issue = 2 | pages = 328–336 | date = October 2007 | pmid = 17964270 | pmc = 2763384 | doi = 10.1016/j.molcel.2007.09.028 }} [68] => [69] => As many as 16% of pre-miRNAs may be altered through nuclear [[RNA editing]].{{cite journal | vauthors = Kawahara Y, Megraw M, Kreider E, Iizasa H, Valente L, Hatzigeorgiou AG, Nishikura K | title = Frequency and fate of microRNA editing in human brain | journal = Nucleic Acids Research | volume = 36 | issue = 16 | pages = 5270–80 | date = September 2008 | pmid = 18684997 | pmc = 2532740 | doi = 10.1093/nar/gkn479 }}{{cite journal | vauthors = Winter J, Jung S, Keller S, Gregory RI, Diederichs S | title = Many roads to maturity: microRNA biogenesis pathways and their regulation | journal = Nature Cell Biology | volume = 11 | issue = 3 | pages = 228–34 | date = March 2009 | pmid = 19255566 | doi = 10.1038/ncb0309-228 | s2cid = 205286318 }}{{cite journal | vauthors = Ohman M | title = A-to-I editing challenger or ally to the microRNA process | journal = Biochimie | volume = 89 | issue = 10 | pages = 1171–6 | date = October 2007 | pmid = 17628290 | doi = 10.1016/j.biochi.2007.06.002 }} Most commonly, [[enzyme]]s known as [[adenosine deaminase]]s acting on RNA (ADARs) catalyze [[adenosine]] to [[inosine]] (A to I) transitions. RNA editing can halt nuclear processing (for example, of pri-miR-142, leading to degradation by the ribonuclease Tudor-SN) and alter downstream processes including cytoplasmic miRNA processing and target specificity (e.g., by changing the seed region of miR-376 in the central nervous system). [70] => [71] => ===Nuclear export=== [72] => [[File:3a6p xpo5 ran miRNA.png|thumb|left|The human exportin-5 protein (red) in complex with [[Ran-GTP]] (yellow) and a pre-microRNA (green), showing two-[[nucleotide]] overhang recognition element (orange). From {{PDB|3A6P}}.]] [73] => Pre-miRNA hairpins are exported from the nucleus in a process involving the nucleocytoplasmic shuttler [[XPO5|Exportin-5]]. This protein, a member of the [[karyopherin|karyopherin family]], recognizes a two-nucleotide overhang left by the RNase III enzyme Drosha at the 3' end of the pre-miRNA hairpin. Exportin-5-mediated transport to the cytoplasm is energy-dependent, using [[guanosine triphosphate]] (GTP) bound to the [[Ran (biology)|Ran]] protein.{{cite journal | vauthors = Murchison EP, Hannon GJ | title = miRNAs on the move: miRNA biogenesis and the RNAi machinery | journal = Current Opinion in Cell Biology | volume = 16 | issue = 3 | pages = 223–9 | date = June 2004 | pmid = 15145345 | doi = 10.1016/j.ceb.2004.04.003 | author-link2 = Gregory Hannon | author-link1 = Elizabeth Murchison }} {{closed access}} [74] => [75] => ===Cytoplasmic processing=== [76] => In the [[cytoplasm]], the pre-miRNA hairpin is cleaved by the RNase III enzyme [[Dicer]].{{cite journal | vauthors = Lund E, Dahlberg JE | title = Substrate selectivity of exportin 5 and Dicer in the biogenesis of microRNAs | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 71 | pages = 59–66 | year = 2006 | pmid = 17381281 | doi = 10.1101/sqb.2006.71.050 | doi-access = free }} This endoribonuclease interacts with 5' and 3' ends of the hairpin{{cite journal | vauthors = Park JE, Heo I, Tian Y, Simanshu DK, Chang H, Jee D, Patel DJ, Kim VN | title = Dicer recognizes the 5' end of RNA for efficient and accurate processing | journal = Nature | volume = 475 | issue = 7355 | pages = 201–5 | date = July 2011 | pmid = 21753850 | pmc = 4693635 | doi = 10.1038/nature10198 }} and cuts away the loop joining the 3' and 5' arms, yielding an imperfect miRNA:miRNA* duplex about 22 nucleotides in length. Overall hairpin length and loop size influence the efficiency of Dicer processing. The imperfect nature of the miRNA:miRNA* pairing also affects cleavage.{{Cite book | vauthors = Ji X | chapter = The Mechanism of RNase III Action: How Dicer Dices | volume = 320 | pages = 99–116 | year = 2008 | pmid = 18268841 | doi = 10.1007/978-3-540-75157-1_5 | isbn = 978-3-540-75156-4 | series = Current Topics in Microbiology and Immunology | title = RNA Interference }} Some of the G-rich pre-miRNAs can potentially adopt the [[G-quadruplex]] structure as an alternative to the canonical stem-loop structure. For example, human pre-miRNA 92b adopts a [[G-quadruplex]] structure which is resistant to the Dicer mediated cleavage in the [[cytoplasm]].{{cite journal | vauthors = Mirihana Arachchilage G, Dassanayake AC, Basu S | title = A potassium ion-dependent RNA structural switch regulates human pre-miRNA 92b maturation | journal = Chemistry & Biology | volume = 22 | issue = 2 | pages = 262–72 | date = February 2015 | pmid = 25641166 | doi = 10.1016/j.chembiol.2014.12.013 | doi-access = free }} Although either strand of the duplex may potentially act as a functional miRNA, only one strand is usually incorporated into the [[RNA-induced silencing complex]] (RISC) where the miRNA and its mRNA target interact. [77] => [78] => While the majority of miRNAs are located within the cell, some miRNAs, commonly known as circulating miRNAs or extracellular miRNAs, have also been found in extracellular environment, including various biological fluids and cell culture media.{{cite journal | doi = 10.1016/j.als.2016.11.007 | volume=10 | issue=2 | title=Extracellular/Circulating MicroRNAs: Release Mechanisms, Functions and Challenges | journal=Achievements in the Life Sciences | pages=175–186| year=2016 | vauthors = Sohel MH | doi-access=free }}{{cite journal | vauthors = Boeckel JN, Reis SM, Leistner D, Thomé CE, Zeiher AM, Fichtlscherer S, Keller T | title = From heart to toe: heart's contribution on peripheral microRNA levels | journal = International Journal of Cardiology | volume = 172 | issue = 3 | pages = 616–7 | date = April 2014 | pmid = 24508494 | doi = 10.1016/j.ijcard.2014.01.082 }} [79] => [80] => ===Biogenesis in plants=== [81] => miRNA biogenesis in plants differs from animal biogenesis mainly in the steps of nuclear processing and export. Instead of being cleaved by two different enzymes, once inside and once outside the nucleus, both cleavages of the plant miRNA are performed by a Dicer homolog, called [[Dicer-like1]] (DL1). DL1 is expressed only in the nucleus of plant cells, which indicates that both reactions take place inside the nucleus. Before plant miRNA:miRNA* duplexes are transported out of the nucleus, its 3' overhangs are methylated by a [[Methyltransferase|RNA methyltransferaseprotein]] called [[Hua-Enhancer1]] (HEN1). The duplex is then transported out of the nucleus to the cytoplasm by a protein called Hasty (HST), an Exportin 5 homolog, where they disassemble and the mature miRNA is incorporated into the RISC.{{cite journal | vauthors = Lelandais-Brière C, Sorin C, Declerck M, Benslimane A, Crespi M, Hartmann C | title = Small RNA diversity in plants and its impact in development | journal = Current Genomics | volume = 11 | issue = 1 | pages = 14–23 | date = March 2010 | pmid = 20808519 | pmc = 2851111 | doi = 10.2174/138920210790217918 }} [82] => [83] => ==RNA-induced silencing complex== [84] => {{Main|RNA-induced silencing complex}} [85] => [86] => The mature miRNA is part of an active RNA-induced silencing complex (RISC) containing Dicer and many associated proteins.{{cite journal | vauthors = Rana TM | title = Illuminating the silence: understanding the structure and function of small RNAs | journal = Nature Reviews Molecular Cell Biology | volume = 8 | issue = 1 | pages = 23–36 | date = January 2007 | pmid = 17183358 | doi = 10.1038/nrm2085 | s2cid = 8966239 }} RISC is also known as a microRNA ribonucleoprotein complex (miRNP);{{cite journal | vauthors = Schwarz DS, Zamore PD | title = Why do miRNAs live in the miRNP? | journal = Genes & Development | volume = 16 | issue = 9 | pages = 1025–31 | date = May 2002 | pmid = 12000786 | doi = 10.1101/gad.992502 | doi-access = free }} A RISC with incorporated miRNA is sometimes referred to as a "miRISC." [87] => [88] => Dicer processing of the pre-miRNA is thought to be coupled with unwinding of the duplex. Generally, only one strand is incorporated into the miRISC, selected on the basis of its thermodynamic instability and weaker base-pairing on the 5' end relative to the other strand.{{cite journal | vauthors = Krol J, Sobczak K, Wilczynska U, Drath M, Jasinska A, Kaczynska D, Krzyzosiak WJ | title = Structural features of microRNA (miRNA) precursors and their relevance to miRNA biogenesis and small interfering RNA/short hairpin RNA design | journal = The Journal of Biological Chemistry | volume = 279 | issue = 40 | pages = 42230–9 | date = October 2004 | pmid = 15292246 | doi = 10.1074/jbc.M404931200 | doi-access = free }}{{cite journal | vauthors = Khvorova A, Reynolds A, Jayasena SD | title = Functional siRNAs and miRNAs exhibit strand bias | journal = Cell | volume = 115 | issue = 2 | pages = 209–16 | date = October 2003 | pmid = 14567918 | doi = 10.1016/S0092-8674(03)00801-8 | doi-access = free }}{{cite journal | vauthors = Schwarz DS, Hutvágner G, Du T, Xu Z, Aronin N, Zamore PD | title = Asymmetry in the assembly of the RNAi enzyme complex | journal = Cell | volume = 115 | issue = 2 | pages = 199–208 | date = October 2003 | pmid = 14567917 | doi = 10.1016/S0092-8674(03)00759-1 | doi-access = free }} The position of the stem-loop may also influence strand choice.{{cite journal | vauthors = Lin SL, Chang D, Ying SY | title = Asymmetry of intronic pre-miRNA structures in functional RISC assembly | journal = Gene | volume = 356 | pages = 32–8 | date = August 2005 | pmid = 16005165 | pmc = 1788082 | doi = 10.1016/j.gene.2005.04.036 }} The other strand, called the passenger strand due to its lower levels in the steady state, is denoted with an asterisk (*) and is normally degraded. In some cases, both strands of the duplex are viable and become functional miRNA that target different mRNA populations.{{cite journal | vauthors = Okamura K, Chung WJ, Lai EC | title = The long and short of inverted repeat genes in animals: microRNAs, mirtrons and hairpin RNAs | journal = Cell Cycle | volume = 7 | issue = 18 | pages = 2840–5 | date = September 2008 | pmid = 18769156 | pmc = 2697033 | doi = 10.4161/cc.7.18.6734 }} [89] => [90] => [[File:MicroRNAs and Argonaute RNA binding.svg|thumb|right|AGO2 (grey) in complex with a microRNA (light blue) and its target mRNA (dark blue)]] [91] => [92] => Members of the [[Argonaute]] (Ago) protein family are central to RISC function. Argonautes are needed for miRNA-induced silencing and contain two conserved RNA binding domains: a PAZ domain that can bind the single stranded 3' end of the mature miRNA and a [[Piwi|PIWI]] domain that structurally resembles [[Ribonuclease H|ribonuclease-H]] and functions to interact with the 5' end of the guide strand. They bind the mature miRNA and orient it for interaction with a target mRNA. Some argonautes, for example human Ago2, cleave target transcripts directly; argonautes may also recruit additional proteins to achieve translational repression.{{cite journal | vauthors = Pratt AJ, MacRae IJ | title = The RNA-induced silencing complex: a versatile gene-silencing machine | journal = The Journal of Biological Chemistry | volume = 284 | issue = 27 | pages = 17897–901 | date = July 2009 | pmid = 19342379 | pmc = 2709356 | doi = 10.1074/jbc.R900012200 | doi-access = free }} The human genome encodes eight argonaute proteins divided by sequence similarities into two families: AGO (with four members present in all mammalian cells and called E1F2C/hAgo in humans), and PIWI (found in the germline and hematopoietic stem cells). [93] => [94] => Additional RISC components include [[TARBP2|TRBP]] [human immunodeficiency virus (HIV) transactivating response RNA (TAR) binding protein],{{cite journal | vauthors = MacRae IJ, Ma E, Zhou M, Robinson CV, Doudna JA | title = In vitro reconstitution of the human RISC-loading complex | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 2 | pages = 512–7 | date = January 2008 | pmid = 18178619 | pmc = 2206567 | doi = 10.1073/pnas.0710869105 | bibcode = 2008PNAS..105..512M | doi-access = free }} PACT (protein activator of the [[interferon]]-induced [[protein kinase]]), the SMN complex, [[Fragile X syndrome|fragile X mental retardation protein]] (FMRP), Tudor staphylococcal nuclease-domain-containing protein (Tudor-SN), the putative DNA [[helicase]] [[MOV10]], and the RNA recognition motif containing protein [[TNRC6B]].{{cite journal | vauthors = Mourelatos Z, Dostie J, Paushkin S, Sharma A, Charroux B, Abel L, [[Juri Rappsilber|Rappsilber J]], Mann M, Dreyfuss G | title = miRNPs: a novel class of ribonucleoproteins containing numerous microRNAs | journal = Genes & Development | volume = 16 | issue = 6 | pages = 720–8 | date = March 2002 | pmid = 11914277 | pmc = 155365 | doi = 10.1101/gad.974702 }}{{cite journal | vauthors = Meister G, Landthaler M, Peters L, Chen PY, Urlaub H, Lührmann R, Tuschl T | title = Identification of novel argonaute-associated proteins | journal = Current Biology | volume = 15 | issue = 23 | pages = 2149–55 | date = December 2005 | pmid = 16289642 | doi = 10.1016/j.cub.2005.10.048 | doi-access = free | bibcode = 2005CBio...15.2149M | hdl = 11858/00-001M-0000-0012-E763-B | hdl-access = free }} [95] => [96] => ===Mode of silencing and regulatory loops=== [97] => Gene silencing may occur either via mRNA degradation or preventing mRNA from being translated. For example, miR16 contains a sequence complementary to the AU-rich element found in the 3'UTR of many unstable mRNAs, such as [[Tumor necrosis factor alpha|TNF alpha]] or [[Granulocyte macrophage colony-stimulating factor|GM-CSF]].{{cite journal | vauthors = Jing Q, Huang S, Guth S, Zarubin T, Motoyama A, Chen J, Di Padova F, Lin SC, Gram H, Han J | title = Involvement of microRNA in AU-rich element-mediated mRNA instability | journal = Cell | volume = 120 | issue = 5 | pages = 623–34 | date = March 2005 | pmid = 15766526 | doi = 10.1016/j.cell.2004.12.038 | doi-access = free }} It has been demonstrated that given complete complementarity between the miRNA and target mRNA sequence, Ago2 can cleave the mRNA and lead to direct mRNA degradation. In the absence of complementarity, silencing is achieved by preventing translation. The relation of miRNA and its target mRNA can be based on the simple negative regulation of a target mRNA, but it seems that a common scenario is the use of a "coherent [[Feed forward (control)|feed-forward]] loop", "mutual negative feedback loop" (also termed double negative loop) and "positive feedback/feed-forward loop". Some miRNAs work as buffers of random gene expression changes arising due to stochastic events in transcription, translation and protein stability. Such regulation is typically achieved by the virtue of negative feedback loops or incoherent feed-forward loop uncoupling protein output from mRNA transcription. [98] => [99] => ==Turnover== [100] => Turnover of mature miRNA is needed for rapid changes in miRNA expression profiles. During miRNA maturation in the cytoplasm, uptake by the Argonaute protein is thought to stabilize the guide strand, while the opposite (* or "passenger") strand is preferentially destroyed. In what has been called a "Use it or lose it" strategy, Argonaute may preferentially retain miRNAs with many targets over miRNAs with few or no targets, leading to degradation of the non-targeting molecules.{{cite journal | vauthors = Kai ZS, Pasquinelli AE | title = MicroRNA assassins: factors that regulate the disappearance of miRNAs | journal = Nature Structural & Molecular Biology | volume = 17 | issue = 1 | pages = 5–10 | date = January 2010 | pmid = 20051982 | doi = 10.1038/nsmb.1762 | pmc = 6417416 }} [101] => [102] => Decay of mature miRNAs in ''[[Caenorhabditis elegans]]'' is mediated by the 5'-to-3' [[exoribonuclease]] [[XRN2]], also known as Rat1p.{{cite journal | vauthors = Chatterjee S, Grosshans H | title = Active turnover modulates mature microRNA activity in Caenorhabditis elegans | journal = Nature | volume = 461 | issue = 7263 | pages = 546–9 | date = September 2009 | pmid = 19734881 | doi = 10.1038/nature08349 | bibcode = 2009Natur.461..546C | s2cid = 4414841 }} In plants, SDN (small RNA degrading nuclease) family members degrade miRNAs in the opposite (3'-to-5') direction. Similar enzymes are encoded in animal genomes, but their roles have not been described. [103] => [104] => Several miRNA modifications affect miRNA stability. As indicated by work in the model organism ''[[Arabidopsis thaliana]]'' (thale cress), mature plant miRNAs appear to be stabilized by the addition of methyl moieties at the 3' end. The 2'-O-conjugated methyl groups block the addition of [[uracil]] (U) residues by [[UTP—glucose-1-phosphate uridylyltransferase|uridyltransferase]] enzymes, a modification that may be associated with miRNA degradation. However, uridylation may also protect some miRNAs; the consequences of this modification are incompletely understood. Uridylation of some animal miRNAs has been reported. Both plant and animal miRNAs may be altered by addition of adenine (A) residues to the 3' end of the miRNA. An extra A added to the end of mammalian [[miR-122]], a liver-enriched miRNA important in [[hepatitis C]], stabilizes the molecule and plant miRNAs ending with an adenine residue have slower decay rates. [105] => [106] => ==Cellular functions== [107] => [[File:MiRNA mechanisms.jpg|thumb|320px|Interaction of microRNA with protein translation process. Several translation repression mechanisms are shown: M1) on the initiation process, preventing assembling of the initiation complex or recruiting the 40S ribosomal subunit; M2) on the ribosome assembly; M3) on the translation process; M7, M8) on the degradation of mRNA.{{cite journal | vauthors = Morozova N, Zinovyev A, Nonne N, Pritchard LL, Gorban AN, Harel-Bellan A | title = Kinetic signatures of microRNA modes of action | journal = RNA | volume = 18 | issue = 9 | pages = 1635–55 | date = September 2012 | pmid = 22850425 | pmc = 3425779 | doi = 10.1261/rna.032284.112 }} 40S and 60S are light and heavy components of the ribosome, 80S is the assembled ribosome bound to mRNA, eIF4F is a translation initiation factor, PABC1 is the Poly-A binding protein, and "cap" is the mRNA cap structure needed for mRNA circularization (which can be the normal m7G-cap or modified A-cap). The initiation of mRNA can proceed in a cap-independent manner, through recruiting 40S to IRES ([[Internal ribosome entry site|Internal Ribosome Entry Site]]) located in 5'UTR region. The actual work of RNA silencing is performed by RISC in which the main catalytic subunit is one of the Argonaute proteins (AGO), and miRNA serves as a template for recognizing specific mRNA sequences. [108] => ]] [109] => The function of miRNAs appears to be in gene regulation. For that purpose, a miRNA is [[complementarity (molecular biology)|complementary]] to a part of one or more [[messenger RNA]]s (mRNAs). Animal miRNAs are usually complementary to a site in the [[3' UTR]] whereas plant miRNAs are usually complementary to coding regions of mRNAs.{{cite journal | vauthors = Wang XJ, Reyes JL, Chua NH, Gaasterland T | title = Prediction and identification of Arabidopsis thaliana microRNAs and their mRNA targets | journal = Genome Biology | volume = 5 | issue = 9 | pages = R65 | year = 2004 | pmid = 15345049 | pmc = 522872 | doi = 10.1186/gb-2004-5-9-r65 | doi-access = free }} Perfect or near perfect base pairing with the target RNA promotes cleavage of the RNA.{{cite journal | vauthors = Kawasaki H, Taira K | title = MicroRNA-196 inhibits HOXB8 expression in myeloid differentiation of HL60 cells | journal = Nucleic Acids Symposium Series | volume = 48 | issue = 1 | pages = 211–2 | year = 2004 | pmid = 17150553 | doi = 10.1093/nass/48.1.211 | doi-access = free }} This is the primary mode of plant miRNAs.{{cite journal | vauthors = Moxon S, Jing R, Szittya G, Schwach F, Rusholme Pilcher RL, Moulton V, Dalmay T | title = Deep sequencing of tomato short RNAs identifies microRNAs targeting genes involved in fruit ripening | journal = Genome Research | volume = 18 | issue = 10 | pages = 1602–9 | date = October 2008 | pmid = 18653800 | pmc = 2556272 | doi = 10.1101/gr.080127.108 }} In animals the match-ups are imperfect. [110] => [111] => For partially complementary microRNAs to recognise their targets, nucleotides 2–7 of the miRNA (its 'seed region') must be perfectly complementary.{{cite journal | vauthors = Mazière P, Enright AJ | title = Prediction of microRNA targets | journal = Drug Discovery Today | volume = 12 | issue = 11–12 | pages = 452–8 | date = June 2007 | pmid = 17532529 | doi = 10.1016/j.drudis.2007.04.002 }} Animal miRNAs inhibit protein translation of the target mRNA{{cite journal | vauthors = Williams AE | title = Functional aspects of animal microRNAs | journal = Cellular and Molecular Life Sciences | volume = 65 | issue = 4 | pages = 545–62 | date = February 2008 | pmid = 17965831 | doi = 10.1007/s00018-007-7355-9 | s2cid = 5708394 }} (this is present but less common in plants). Partially complementary microRNAs can also speed up [[deadenylation]], causing mRNAs to be degraded sooner.{{cite journal | vauthors = Eulalio A, Huntzinger E, Nishihara T, Rehwinkel J, Fauser M, Izaurralde E | title = Deadenylation is a widespread effect of miRNA regulation | journal = RNA | volume = 15 | issue = 1 | pages = 21–32 | date = January 2009 | pmid = 19029310 | pmc = 2612776 | doi = 10.1261/rna.1399509 }} While degradation of miRNA-targeted mRNA is well documented, whether or not translational repression is accomplished through mRNA degradation, translational inhibition, or a combination of the two is hotly debated. Recent work on [[mir-430 microRNA precursor family|miR-430]] in zebrafish, as well as on bantam-miRNA and [[miR-9]] in ''Drosophila'' cultured cells, shows that translational repression is caused by the disruption of [[Eukaryotic translation#Initiation|translation initiation]], independent of mRNA deadenylation.{{cite journal | vauthors = Bazzini AA, Lee MT, Giraldez AJ | title = Ribosome profiling shows that miR-430 reduces translation before causing mRNA decay in zebrafish | journal = Science | volume = 336 | issue = 6078 | pages = 233–7 | date = April 2012 | pmid = 22422859 | pmc = 3547538 | doi = 10.1126/science.1215704 | bibcode = 2012Sci...336..233B }}{{cite journal | vauthors = Djuranovic S, Nahvi A, Green R | title = miRNA-mediated gene silencing by translational repression followed by mRNA deadenylation and decay | journal = Science | volume = 336 | issue = 6078 | pages = 237–40 | date = April 2012 | pmid = 22499947 | pmc = 3971879 | doi = 10.1126/science.1215691 | bibcode = 2012Sci...336..237D }} [112] => [113] => miRNAs occasionally also cause [[Histone#Chromatin regulation|histone modification]] and [[DNA methylation]] of [[Promoter (biology)|promoter]] sites, which affects the expression of target genes.{{cite journal | vauthors = Tan Y, Zhang B, Wu T, Skogerbø G, Zhu X, Guo X, He S, Chen R | title = Transcriptional inhibiton of Hoxd4 expression by miRNA-10a in human breast cancer cells | journal = BMC Molecular Biology | volume = 10 | issue = 1 | pages = 12 | date = February 2009 | pmid = 19232136 | pmc = 2680403 | doi = 10.1186/1471-2199-10-12 | doi-access = free }}{{cite journal | vauthors = Hawkins PG, Morris KV | title = RNA and transcriptional modulation of gene expression | journal = Cell Cycle | volume = 7 | issue = 5 | pages = 602–7 | date = March 2008 | pmid = 18256543 | pmc = 2877389 | doi = 10.4161/cc.7.5.5522 }} [114] => [115] => Nine mechanisms of miRNA action are described and assembled in a unified mathematical model: [116] => * Cap-40S initiation inhibition; [117] => * 60S Ribosomal unit joining inhibition; [118] => * Elongation inhibition; [119] => * Ribosome drop-off (premature termination); [120] => * Co-translational nascent protein degradation; [121] => * Sequestration in [[P-bodies]]; [122] => * mRNA decay (destabilisation); [123] => * mRNA cleavage; [124] => * Transcriptional inhibition through microRNA-mediated chromatin reorganization followed by gene silencing. [125] => It is often impossible to discern these mechanisms using experimental data about stationary reaction rates. Nevertheless, they are differentiated in dynamics and have different ''kinetic signatures''. [126] => [127] => Unlike plant microRNAs, the animal microRNAs target diverse genes. However, genes involved in functions common to all cells, such as gene expression, have relatively fewer microRNA target sites and seem to be under selection to avoid targeting by microRNAs.{{cite journal | vauthors = Stark A, Brennecke J, Bushati N, Russell RB, Cohen SM | title = Animal MicroRNAs confer robustness to gene expression and have a significant impact on 3'UTR evolution | journal = Cell | volume = 123 | issue = 6 | pages = 1133–46 | date = December 2005 | pmid = 16337999 | doi = 10.1016/j.cell.2005.11.023 | doi-access = free }} There is a strong correlation between ''ITPR'' gene regulations and mir-92 and mir-19.{{cite journal | vauthors = He L, Hannon GJ | title = MicroRNAs: small RNAs with a big role in gene regulation | journal = Nature Reviews. Genetics | volume = 5 | issue = 7 | pages = 522–531 | date = July 2004 | doi = 10.1038/nrg1379 | pmid = 15211354 | s2cid = 5270062 }} [128] => [129] => dsRNA can also activate [[gene expression]], a mechanism that has been termed "small RNA-induced gene activation" or [[RNA activation|RNAa]]. dsRNAs targeting gene promoters can induce potent transcriptional activation of associated genes. This was demonstrated in human cells using synthetic dsRNAs termed small activating RNAs ([[saRNA]]s),{{cite book | chapter-url = http://www.horizonpress.com/rnareg | vauthors = Li LC |chapter=Small RNA-Mediated Gene Activation|title=RNA and the Regulation of Gene Expression: A Hidden Layer of Complexity | veditors = Morris KV | url = {{google books |plainurl=y |id=r67Lrf9r9XEC}}|year=2008|publisher=Horizon Scientific Press|isbn=978-1-904455-25-7}} but has also been demonstrated for endogenous microRNA.{{cite journal | vauthors = Place RF, Li LC, Pookot D, Noonan EJ, Dahiya R | title = MicroRNA-373 induces expression of genes with complementary promoter sequences | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 5 | pages = 1608–13 | date = February 2008 | pmid = 18227514 | pmc = 2234192 | doi = 10.1073/pnas.0707594105 | bibcode = 2008PNAS..105.1608P | doi-access = free }} [130] => [131] => Interactions between microRNAs and complementary sequences on genes and even [[pseudogene]]s that share [[sequence homology]] are thought to be a back channel of communication regulating expression levels between paralogous genes (genes having a similar structure indicating divergence from a common ancestral gene). Given the name "competing endogenous RNAs" ([[ceRNA]]s), these microRNAs bind to "microRNA response elements" on genes and pseudogenes and may provide another explanation for the persistence of [[non-coding DNA]].{{cite journal | vauthors = Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP | title = A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? | journal = Cell | volume = 146 | issue = 3 | pages = 353–8 | date = August 2011 | pmid = 21802130 | pmc = 3235919 | doi = 10.1016/j.cell.2011.07.014 }} [132] => [133] => miRNAs are also found as [[Extracellular RNA|extracellular]] '''circulating miRNAs'''.{{cite journal |vauthors=Kumar S, Reddy PH |title=Are circulating microRNAs peripheral biomarkers for Alzheimer's disease? |journal=Biochim Biophys Acta |volume=1862 |issue=9 |pages=1617–27 |date=September 2016 |pmid=27264337 |pmc=5343750 |doi=10.1016/j.bbadis.2016.06.001 |url=}} Circulating miRNAs are released into body fluids including blood and [[cerebrospinal fluid]] and have the potential to be available as [[biomarker]]s in a number of diseases.{{cite journal |vauthors=van den Berg MM, Krauskopf J, Ramaekers JG, et al. |title=Circulating microRNAs as potential biomarkers for psychiatric and neurodegenerative disorders |journal=Prog Neurobiol |volume=185 |issue= |pages=101732 |date=February 2020 |pmid=31816349 |doi=10.1016/j.pneurobio.2019.101732 |url=|doi-access=free }}Some researches show that mRNA cargo of exosomes may have a role in implantation, they can savage an adhesion between trophoblast and endometrium or support the adhesion by down regulating or up regulating expression of genes involved in adhesion/invasion.{{cite journal | vauthors = Cuman C, Van Sinderen M, Gantier MP, Rainczuk K, Sorby K, Rombauts L, Osianlis T, Dimitriadis E | title = Human Blastocyst Secreted microRNA Regulate Endometrial Epithelial Cell Adhesion | journal = eBioMedicine | volume = 2 | issue = 10 | pages = 1528–1535 | date = October 2015 | pmid = 26629549 | pmc = 4634783 | doi = 10.1016/j.ebiom.2015.09.003 }} [134] => [135] => Moreover, miRNA as [[miR-183/96/182]] seems to play a key role in [[circadian rhythm]].{{cite journal | vauthors = Zhou L, Miller C, Miraglia LJ, Romero A, Mure LS, Panda S, Kay SA | title = A genome-wide microRNA screen identifies the microRNA-183/96/182 cluster as a modulator of circadian rhythms | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 118 | issue = 1 | pages = e2020454118 | date = January 2021 | pmid = 33443164 | pmc = 7817116 | doi = 10.1073/pnas.2020454118 | bibcode = 2021PNAS..11820454Z | s2cid = 230713808| doi-access = free }} [136] => *{{cite magazine |date=6 January 2021 |title=MicroRNAs Play Key Role in Regulation of Circadian Rhythms |magazine=Science News |url=http://www.sci-news.com/biology/micrornas-key-role-regulation-circadian-rhythms-09221.html}} [137] => [138] => ==Evolution== [139] => [140] => miRNAs are well [[conserved sequence|conserved]] in both plants and animals, and are thought to be a vital and evolutionarily ancient component of gene regulation.{{cite journal | vauthors = Axtell MJ, Bartel DP | title = Antiquity of microRNAs and their targets in land plants | journal = The Plant Cell | volume = 17 | issue = 6 | pages = 1658–73 | date = June 2005 | pmid = 15849273 | pmc = 1143068 | doi = 10.1105/tpc.105.032185 }}{{cite journal | vauthors = Tanzer A, Stadler PF | title = Molecular evolution of a microRNA cluster | journal = Journal of Molecular Biology | volume = 339 | issue = 2 | pages = 327–35 | date = May 2004 | pmid = 15136036 | doi = 10.1016/j.jmb.2004.03.065 | citeseerx = 10.1.1.194.1598 }}{{cite journal | vauthors = Chen K, Rajewsky N | title = The evolution of gene regulation by transcription factors and microRNAs | journal = Nature Reviews Genetics | volume = 8 | issue = 2 | pages = 93–103 | date = February 2007 | pmid = 17230196 | doi = 10.1038/nrg1990 | s2cid = 174231 }}{{cite journal | vauthors = Lee CT, Risom T, Strauss WM | title = Evolutionary conservation of microRNA regulatory circuits: an examination of microRNA gene complexity and conserved microRNA-target interactions through metazoan phylogeny | journal = DNA and Cell Biology | volume = 26 | issue = 4 | pages = 209–18 | date = April 2007 | pmid = 17465887 | doi = 10.1089/dna.2006.0545 }} While core components of the microRNA pathway are conserved between [[plant]]s and [[animal]]s, miRNA repertoires in the two kingdoms appear to have emerged independently with different primary modes of action.{{cite journal | vauthors = Shabalina SA, Koonin EV | title = Origins and evolution of eukaryotic RNA interference | journal = Trends in Ecology & Evolution | volume = 23 | issue = 10 | pages = 578–87 | date = October 2008 | pmid = 18715673 | pmc = 2695246 | doi = 10.1016/j.tree.2008.06.005 }}{{cite journal | vauthors = Axtell MJ, Westholm JO, Lai EC | title = Vive la différence: biogenesis and evolution of microRNAs in plants and animals | journal = Genome Biology | volume = 12 | issue = 4 | pages = 221 | date = 2011 | pmid = 21554756 | pmc = 3218855 | doi = 10.1186/gb-2011-12-4-221 | doi-access = free }} [141] => [142] => microRNAs are useful [[Phylogenetics|phylogenetic]] markers because of their apparently low rate of evolution. microRNAs' origin as a regulatory mechanism developed from previous RNAi machinery that was initially used as a defense against exogenous genetic material such as viruses.{{cite journal | vauthors = Pashkovskiy PP, Ryazansky SS | title = Biogenesis, evolution, and functions of plant microRNAs | journal = Biochemistry. Biokhimiia | volume = 78 | issue = 6 | pages = 627–37 | date = June 2013 | pmid = 23980889 | doi = 10.1134/S0006297913060084 | s2cid = 12025420 }} Their origin may have permitted the development of morphological innovation, and by making gene expression more specific and 'fine-tunable', permitted the genesis of complex organs and perhaps, ultimately, complex life.{{cite journal | vauthors = Peterson KJ, Dietrich MR, McPeek MA | title = MicroRNAs and metazoan macroevolution: insights into canalization, complexity, and the Cambrian explosion | journal = BioEssays | volume = 31 | issue = 7 | pages = 736–47 | date = July 2009 | pmid = 19472371 | doi = 10.1002/bies.200900033 | s2cid = 15364875 | doi-access = free }} Rapid bursts of morphological innovation are generally associated with a high rate of microRNA accumulation.{{cite journal | vauthors = Wheeler BM, Heimberg AM, Moy VN, Sperling EA, Holstein TW, Heber S, Peterson KJ | title = The deep evolution of metazoan microRNAs | journal = Evolution & Development | volume = 11 | issue = 1 | pages = 50–68 | year = 2009 | pmid = 19196333 | doi = 10.1111/j.1525-142X.2008.00302.x | s2cid = 14924603 }}{{cite journal | vauthors = Heimberg AM, Sempere LF, Moy VN, Donoghue PC, Peterson KJ | title = MicroRNAs and the advent of vertebrate morphological complexity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 8 | pages = 2946–50 | date = February 2008 | pmid = 18287013 | pmc = 2268565 | doi = 10.1073/pnas.0712259105 | bibcode = 2008PNAS..105.2946H | doi-access = free }} [143] => [144] => New microRNAs are created in multiple ways. Novel microRNAs can originate from the random formation of hairpins in "non-coding" sections of DNA (i.e. [[Intron|introns or intergene]] regions), but also by the duplication and modification of existing microRNAs. microRNAs can also form from inverted duplications of protein-coding sequences, which allows for the creation of a foldback hairpin structure.{{cite journal | vauthors = Allen E, Xie Z, Gustafson AM, Sung GH, Spatafora JW, Carrington JC | title = Evolution of microRNA genes by inverted duplication of target gene sequences in Arabidopsis thaliana | journal = Nature Genetics | volume = 36 | issue = 12 | pages = 1282–90 | date = December 2004 | pmid = 15565108 | doi = 10.1038/ng1478 | s2cid = 11997028 }} The rate of evolution (i.e. nucleotide substitution) in recently originated microRNAs is comparable to that elsewhere in the non-coding DNA, implying evolution by neutral drift; however, older microRNAs have a much lower rate of change (often less than one substitution per hundred million years), suggesting that once a microRNA gains a function, it undergoes purifying selection. Individual regions within an miRNA gene face different evolutionary pressures, where regions that are vital for processing and function have higher levels of conservation.{{cite journal | vauthors = Warthmann N, Das S, Lanz C, Weigel D | title = Comparative analysis of the MIR319a microRNA locus in Arabidopsis and related Brassicaceae | journal = Molecular Biology and Evolution | volume = 25 | issue = 5 | pages = 892–902 | date = May 2008 | pmid = 18296705 | doi = 10.1093/molbev/msn029 | doi-access = free }} At this point, a microRNA is rarely lost from an animal's genome, although newer microRNAs (thus presumably non-functional) are frequently lost.{{cite journal | vauthors = Nozawa M, Miura S, Nei M | title = Origins and evolution of microRNA genes in Drosophila species | journal = Genome Biology and Evolution | volume = 2 | pages = 180–9 | date = July 2010 | pmid = 20624724 | pmc = 2942034 | doi = 10.1093/gbe/evq009 }} In ''[[Arabidopsis thaliana]]'', the net flux of miRNA genes has been predicted to be between 1.2 and 3.3 genes per million years.{{cite journal | vauthors = Fahlgren N, Jogdeo S, Kasschau KD, Sullivan CM, Chapman EJ, Laubinger S, Smith LM, Dasenko M, Givan SA, Weigel D, Carrington JC | title = MicroRNA gene evolution in Arabidopsis lyrata and Arabidopsis thaliana | journal = The Plant Cell | volume = 22 | issue = 4 | pages = 1074–89 | date = April 2010 | pmid = 20407027 | pmc = 2879733 | doi = 10.1105/tpc.110.073999 }} This makes them a valuable phylogenetic marker, and they are being looked upon as a possible solution to outstanding phylogenetic problems such as the relationships of [[arthropod]]s.{{cite journal | vauthors = Caravas J, Friedrich M | title = Of mites and millipedes: recent progress in resolving the base of the arthropod tree | journal = BioEssays | volume = 32 | issue = 6 | pages = 488–95 | date = June 2010 | pmid = 20486135 | doi = 10.1002/bies.201000005 | s2cid = 20548122 }} On the other hand, in multiple cases microRNAs correlate poorly with phylogeny, and it is possible that their phylogenetic concordance largely reflects a limited sampling of microRNAs.{{cite journal | vauthors = Kenny NJ, Namigai EK, Marlétaz F, Hui JH, Shimeld SM | title = Draft genome assemblies and predicted microRNA complements of the intertidal lophotrochozoans Patella vulgata (Mollusca, Patellogastropoda) and Spirobranchus (Pomatoceros) lamarcki (Annelida, Serpulida) | journal = Marine Genomics | volume = 24 | pages = 139–46 | date = December 2015 | pmid = 26319627 | doi = 10.1016/j.margen.2015.07.004 | number = 2 | bibcode = 2015MarGn..24..139K | url = https://ora.ox.ac.uk/objects/uuid:ace9e039-b307-47f1-839c-3a28e189af64 }} [145] => [146] => microRNAs feature in the [[genome]]s of most eukaryotic organisms, from the [[brown algae]]{{cite journal | vauthors = Cock JM, Sterck L, Rouzé P, Scornet D, Allen AE, Amoutzias G, Anthouard V, Artiguenave F, Aury JM, Badger JH, Beszteri B, Billiau K, Bonnet E, Bothwell JH, Bowler C, Boyen C, Brownlee C, Carrano CJ, Charrier B, Cho GY, Coelho SM, Collén J, Corre E, Da Silva C, Delage L, Delaroque N, Dittami SM, Doulbeau S, Elias M, Farnham G, Gachon CM, Gschloessl B, Heesch S, Jabbari K, Jubin C, Kawai H, Kimura K, Kloareg B, Küpper FC, Lang D, Le Bail A, Leblanc C, Lerouge P, Lohr M, Lopez PJ, Martens C, Maumus F, Michel G, Miranda-Saavedra D, Morales J, Moreau H, Motomura T, Nagasato C, Napoli CA, Nelson DR, Nyvall-Collén P, Peters AF, Pommier C, Potin P, Poulain J, Quesneville H, Read B, Rensing SA, Ritter A, Rousvoal S, Samanta M, Samson G, Schroeder DC, Ségurens B, Strittmatter M, Tonon T, Tregear JW, Valentin K, von Dassow P, Yamagishi T, Van de Peer Y, Wincker P | title = The Ectocarpus genome and the independent evolution of multicellularity in brown algae | journal = Nature | volume = 465 | issue = 7298 | pages = 617–21 | date = June 2010 | pmid = 20520714 | doi = 10.1038/nature09016 | bibcode = 2010Natur.465..617C | doi-access = free }} to the animals. However, the difference in how these microRNAs function and the way they are processed suggests that microRNAs arose independently in plants and animals.{{cite journal | vauthors = Cuperus JT, Fahlgren N, Carrington JC | title = Evolution and functional diversification of MIRNA genes | journal = The Plant Cell | volume = 23 | issue = 2 | pages = 431–42 | date = February 2011 | pmid = 21317375 | pmc = 3077775 | doi = 10.1105/tpc.110.082784 }} [147] => [148] => Focusing on the animals, the genome of ''[[Mnemiopsis leidyi]]''{{cite journal | vauthors = Ryan JF, Pang K, Schnitzler CE, Nguyen AD, Moreland RT, Simmons DK, Koch BJ, Francis WR, Havlak P, Smith SA, Putnam NH, Haddock SH, Dunn CW, Wolfsberg TG, Mullikin JC, Martindale MQ, Baxevanis AD | title = The genome of the ctenophore Mnemiopsis leidyi and its implications for cell type evolution | journal = Science | volume = 342 | issue = 6164 | pages = 1242592 | date = December 2013 | pmid = 24337300 | pmc = 3920664 | doi = 10.1126/science.1242592 | author12-link = Steven Haddock }} appears to lack recognizable microRNAs, as well as the nuclear proteins [[Drosha]] and [[Pasha (protein)|Pasha]], which are critical to canonical microRNA biogenesis. It is the only animal thus far reported to be missing Drosha. MicroRNAs play a vital role in the regulation of gene expression in all non-ctenophore animals investigated thus far except for ''[[Trichoplax adhaerens]]'', the first known member of the phylum [[Placozoa]].{{cite journal | vauthors = Maxwell EK, Ryan JF, Schnitzler CE, Browne WE, Baxevanis AD | title = MicroRNAs and essential components of the microRNA processing machinery are not encoded in the genome of the ctenophore Mnemiopsis leidyi | journal = BMC Genomics | volume = 13 | issue = 1 | pages = 714 | date = December 2012 | pmid = 23256903 | pmc = 3563456 | doi = 10.1186/1471-2164-13-714 | doi-access = free }} [149] => [150] => Across all species, in excess of 5000 different miRNAs had been identified by March 2010.{{cite journal | vauthors = Dimond PF |date=15 March 2010 |access-date=10 July 2010 |title=miRNAs' Therapeutic Potential | journal = Genetic Engineering & Biotechnology News |volume=30 |issue=6 |page=1 |url=http://www.genengnews.com/gen-articles/mirnas-therapeutic-potential/3216/ |archive-url=https://web.archive.org/web/20100719042114/http://www.genengnews.com/gen-articles/mirnas-therapeutic-potential/3216/ |archive-date=19 July 2010 |url-status=dead }} Whilst short RNA sequences (50 – hundreds of base pairs) of a broadly comparable function occur in bacteria, bacteria lack true microRNAs.{{cite journal | vauthors = Tjaden B, Goodwin SS, Opdyke JA, Guillier M, Fu DX, Gottesman S, Storz G | title = Target prediction for small, noncoding RNAs in bacteria | journal = Nucleic Acids Research | volume = 34 | issue = 9 | pages = 2791–802 | year = 2006 | pmid = 16717284 | pmc = 1464411 | doi = 10.1093/nar/gkl356 }} [151] => [152] => ==Experimental detection and manipulation== [153] => While researchers focused on miRNA expression in physiological and pathological processes, various technical variables related to microRNA isolation emerged. The stability of stored miRNA samples has been questioned. microRNAs degrade much more easily than mRNAs, partly due to their length, but also because of ubiquitously present [[Ribonuclease|RNases]]. This makes it necessary to cool samples on ice and use [[Ribonuclease|RNase]]-free equipment.{{cite journal | vauthors = Liu CG, Calin GA, Volinia S, Croce CM | title = MicroRNA expression profiling using microarrays | journal = Nature Protocols | volume = 3 | issue = 4 | pages = 563–78 | year = 2008 | pmid = 18388938 | doi = 10.1038/nprot.2008.14 | s2cid = 2441105 }} [154] => [155] => microRNA expression can be quantified in a two-step [[polymerase chain reaction]] process of modified [[RT-PCR]] followed by [[quantitative PCR]]. Variations of this method achieve absolute or relative quantification.{{cite journal | vauthors = Chen C, Ridzon DA, Broomer AJ, Zhou Z, Lee DH, Nguyen JT, Barbisin M, Xu NL, Mahuvakar VR, Andersen MR, Lao KQ, Livak KJ, Guegler KJ | title = Real-time quantification of microRNAs by stem-loop RT-PCR | journal = Nucleic Acids Research | volume = 33 | issue = 20 | pages = e179 | date = November 2005 | pmid = 16314309 | pmc = 1292995 | doi = 10.1093/nar/gni178 }} miRNAs can also be hybridized to [[microarray]]s, slides or chips with probes to hundreds or thousands of miRNA targets, so that relative levels of miRNAs can be determined in different samples.{{cite journal | vauthors = Shingara J, Keiger K, Shelton J, Laosinchai-Wolf W, Powers P, Conrad R, Brown D, Labourier E | title = An optimized isolation and labeling platform for accurate microRNA expression profiling | journal = RNA | volume = 11 | issue = 9 | pages = 1461–70 | date = September 2005 | pmid = 16043497 | pmc = 1370829 | doi = 10.1261/rna.2610405 }} microRNAs can be both discovered and profiled by high-throughput sequencing methods ([[MicroRNA Sequencing|microRNA sequencing]]).{{cite journal | vauthors = Buermans HP, Ariyurek Y, van Ommen G, den Dunnen JT, 't Hoen PA | title = New methods for next generation sequencing based microRNA expression profiling | journal = BMC Genomics | volume = 11 | pages = 716 | date = December 2010 | pmid = 21171994 | pmc = 3022920 | doi = 10.1186/1471-2164-11-716 | doi-access = free }} The activity of an miRNA can be experimentally inhibited using a [[locked nucleic acid]] (LNA) [[oligonucleotide|oligo]], a [[Morpholino]] oligo{{cite journal | vauthors = Kloosterman WP, Wienholds E, Ketting RF, Plasterk RH | title = Substrate requirements for let-7 function in the developing zebrafish embryo | journal = Nucleic Acids Research | volume = 32 | issue = 21 | pages = 6284–91 | year = 2004 | pmid = 15585662 | pmc = 535676 | doi = 10.1093/nar/gkh968 }}{{cite journal | vauthors = Flynt AS, Li N, Thatcher EJ, Solnica-Krezel L, Patton JG | title = Zebrafish miR-214 modulates Hedgehog signaling to specify muscle cell fate | journal = Nature Genetics | volume = 39 | issue = 2 | pages = 259–63 | date = February 2007 | pmid = 17220889 | doi = 10.1038/ng1953 | pmc = 3982799 }} or a 2'-O-methyl RNA oligo.{{cite journal | vauthors = Meister G, Landthaler M, Dorsett Y, Tuschl T | title = Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing | journal = RNA | volume = 10 | issue = 3 | pages = 544–50 | date = March 2004 | pmid = 14970398 | pmc = 1370948 | doi = 10.1261/rna.5235104 }} A specific miRNA can be silenced by a complementary [[antagomir]]. microRNA maturation can be inhibited at several points by steric-blocking oligos.{{cite journal | vauthors = Kloosterman WP, Lagendijk AK, Ketting RF, Moulton JD, Plasterk RH | title = Targeted inhibition of miRNA maturation with morpholinos reveals a role for miR-375 in pancreatic islet development | journal = PLOS Biology | volume = 5 | issue = 8 | pages = e203 | date = August 2007 | pmid = 17676975 | pmc = 1925136 | doi = 10.1371/journal.pbio.0050203 | doi-access = free }}{{cite journal | vauthors = Gebert LF, Rebhan MA, Crivelli SE, Denzler R, Stoffel M, Hall J | title = Miravirsen (SPC3649) can inhibit the biogenesis of miR-122 | journal = Nucleic Acids Research | volume = 42 | issue = 1 | pages = 609–21 | date = January 2014 | pmid = 24068553 | pmc = 3874169 | doi = 10.1093/nar/gkt852 }} The miRNA target site of an mRNA transcript can also be blocked by a steric-blocking oligo.{{cite journal | vauthors = Choi WY, Giraldez AJ, Schier AF | title = Target protectors reveal dampening and balancing of Nodal agonist and antagonist by miR-430 | journal = Science | volume = 318 | issue = 5848 | pages = 271–4 | date = October 2007 | pmid = 17761850 | doi = 10.1126/science.1147535 | bibcode = 2007Sci...318..271C | s2cid = 30461594 | doi-access = free }} For the "in situ" detection of miRNA, LNA{{cite journal | vauthors = You Y, Moreira BG, Behlke MA, Owczarzy R | title = Design of LNA probes that improve mismatch discrimination | journal = Nucleic Acids Research | volume = 34 | issue = 8 | pages = e60 | date = May 2006 | pmid = 16670427 | pmc = 1456327 | doi = 10.1093/nar/gkl175 }} or Morpholino{{cite journal | vauthors = Lagendijk AK, Moulton JD, Bakkers J | title = Revealing details: whole mount microRNA in situ hybridization protocol for zebrafish embryos and adult tissues | journal = Biology Open | volume = 1 | issue = 6 | pages = 566–9 | date = June 2012 | pmid = 23213449 | pmc = 3509442 | doi = 10.1242/bio.2012810 }} probes can be used. The locked conformation of LNA results in enhanced hybridization properties and increases sensitivity and selectivity, making it ideal for detection of short miRNA.{{cite journal | vauthors = Kaur H, Arora A, Wengel J, Maiti S | title = Thermodynamic, counterion, and hydration effects for the incorporation of locked nucleic acid nucleotides into DNA duplexes | journal = Biochemistry | volume = 45 | issue = 23 | pages = 7347–55 | date = June 2006 | pmid = 16752924 | doi = 10.1021/bi060307w }} [156] => [157] => High-throughput quantification of miRNAs is error prone, for the larger variance (compared to [[Messenger rna|mRNAs]]) that comes with methodological problems. [[Messenger rna|mRNA]]-expression is therefore often analyzed to check for miRNA-effects in their levels (e.g. in{{cite journal | vauthors = Nielsen JA, Lau P, Maric D, Barker JL, Hudson LD | title = Integrating microRNA and mRNA expression profiles of neuronal progenitors to identify regulatory networks underlying the onset of cortical neurogenesis | journal = BMC Neuroscience | volume = 10 | pages = 98 | date = August 2009 | pmid = 19689821 | pmc = 2736963 | doi = 10.1186/1471-2202-10-98 | doi-access = free }}). Databases can be used to pair [[Messenger rna|mRNA]]- and miRNA-data that predict miRNA-targets based on their base sequence.{{cite journal | vauthors = Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP | title = MicroRNA targeting specificity in mammals: determinants beyond seed pairing | journal = Molecular Cell | volume = 27 | issue = 1 | pages = 91–105 | date = July 2007 | pmid = 17612493 | pmc = 3800283 | doi = 10.1016/j.molcel.2007.06.017 }}{{cite journal | vauthors = Griffiths-Jones S, Saini HK, van Dongen S, Enright AJ | title = miRBase: tools for microRNA genomics | journal = Nucleic Acids Research | volume = 36 | issue = Database issue | pages = D154–8 | date = January 2008 | pmid = 17991681 | pmc = 2238936 | doi = 10.1093/nar/gkm952 }} While this is usually done after miRNAs of interest have been detected (e. g. because of high expression levels), ideas for analysis tools that integrate [[Messenger rna|mRNA]]- and miRNA-expression information have been proposed.{{cite journal | vauthors = Nam S, Li M, Choi K, Balch C, Kim S, Nephew KP | title = MicroRNA and mRNA integrated analysis (MMIA): a web tool for examining biological functions of microRNA expression | journal = Nucleic Acids Research | volume = 37 | issue = Web Server issue | pages = W356–62 | date = July 2009 | pmid = 19420067 | pmc = 2703907 | doi = 10.1093/nar/gkp294 }}{{cite journal | vauthors = Artmann S, Jung K, Bleckmann A, Beissbarth T | title = Detection of simultaneous group effects in microRNA expression and related target gene sets | journal = PLOS ONE | volume = 7 | issue = 6 | pages = e38365 | year = 2012 | pmid = 22723856 | pmc = 3378551 | doi = 10.1371/journal.pone.0038365 | veditors = Provero P | bibcode = 2012PLoSO...738365A | doi-access = free }} [158] => [159] => ==Human and animal diseases== [160] => Just as miRNA is involved in the normal functioning of eukaryotic cells, so has dysregulation of miRNA been associated with disease. A manually curated, publicly available database, miR2Disease, documents known relationships between miRNA dysregulation and human disease.{{cite journal | vauthors = Jiang Q, Wang Y, Hao Y, Juan L, Teng M, Zhang X, Li M, Wang G, Liu Y | title = miR2Disease: a manually curated database for microRNA deregulation in human disease | journal = Nucleic Acids Research | volume = 37 | issue = Database issue | pages = D98–104 | date = January 2009 | pmid = 18927107 | pmc = 2686559 | doi = 10.1093/nar/gkn714 | series = 37 }} [161] => [162] => ===Inherited diseases=== [163] => A mutation in the seed region of miR-96 causes hereditary progressive hearing loss.{{cite journal | vauthors = Mencía A, Modamio-Høybjør S, Redshaw N, Morín M, Mayo-Merino F, Olavarrieta L, Aguirre LA, del Castillo I, Steel KP, Dalmay T, Moreno F, Moreno-Pelayo MA | title = Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss | journal = Nature Genetics | volume = 41 | issue = 5 | pages = 609–13 | date = May 2009 | pmid = 19363479 | doi = 10.1038/ng.355 | s2cid = 11113852 }} [164] => [165] => A mutation in the seed region of miR-184 causes hereditary keratoconus with anterior polar cataract.{{cite journal | vauthors = Hughes AE, Bradley DT, Campbell M, Lechner J, Dash DP, Simpson DA, Willoughby CE | title = Mutation altering the miR-184 seed region causes familial keratoconus with cataract | journal = American Journal of Human Genetics | volume = 89 | issue = 5 | pages = 628–33 | date = November 2011 | pmid = 21996275 | pmc = 3213395 | doi = 10.1016/j.ajhg.2011.09.014 }} [166] => [167] => Deletion of the miR-17~92 cluster causes skeletal and growth defects.{{cite journal | vauthors = de Pontual L, Yao E, Callier P, Faivre L, Drouin V, Cariou S, Van Haeringen A, Geneviève D, Goldenberg A, Oufadem M, Manouvrier S, Munnich A, Vidigal JA, Vekemans M, Lyonnet S, Henrion-Caude A, Ventura A, Amiel J | title = Germline deletion of the miR-17~92 cluster causes skeletal and growth defects in humans | journal = Nature Genetics | volume = 43 | issue = 10 | pages = 1026–30 | date = September 2011 | pmid = 21892160 | pmc = 3184212 | doi = 10.1038/ng.915 }} [168] => [169] => ===Cancer=== [170] => [[Image:Role of miRNA in a cancer cell.svg|right|thumb|Role of miRNA in a cancer cell]] [171] => [172] => The first human disease known to be associated with miRNA deregulation was [[chronic lymphocytic leukemia]].{{cite journal | vauthors = Calin GA, Liu CG, Sevignani C, Ferracin M, Felli N, Dumitru CD, Shimizu M, Cimmino A, Zupo S, Dono M, Dell'Aquila ML, Alder H, Rassenti L, Kipps TJ, Bullrich F, Negrini M, Croce CM | title = MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 32 | pages = 11755–11760 | date = August 2004 | pmid = 15284443 | pmc = 511048 | doi = 10.1073/pnas.0404432101 | doi-access = free | bibcode = 2004PNAS..10111755C }} Many other miRNAs also have links with cancer and accordingly are sometimes referred to as "[[oncomir]]s".{{cite journal | vauthors = Velle A, Pesenti C, Grassi T, Beltrame L, Martini P, Jaconi M, Agostinis F, Calura E, Katsaros D, Borella F, Fruscio R, D'Incalci M, Marchini S, Romualdi C | title = A comprehensive investigation of histotype-specific microRNA and their variants in Stage I epithelial ovarian cancers | journal = International Journal of Cancer | volume = 152 | issue = 9 | pages = 1989–2001 | date = May 2023 | pmid = 36541726 | doi = 10.1002/ijc.34408 | s2cid = 255034585 | doi-access = free }} In malignant B cells miRNAs participate in pathways fundamental to B cell development like [[B-cell receptor]] (BCR) signalling, B-cell migration/adhesion, cell-cell interactions in immune niches and the production and class-switching of immunoglobulins. MiRNAs influence B cell maturation, generation of pre-, marginal zone, follicular, B1, plasma and memory B cells.{{cite journal | vauthors = Kyriakidis I, Kyriakidis K, Tsezou A | title = MicroRNAs and the Diagnosis of Childhood Acute Lymphoblastic Leukemia: Systematic Review, Meta-Analysis and Re-Analysis with Novel Small RNA-Seq Tools | journal = Cancers | volume = 14 | issue = 16 | pages = 3976 | date = August 2022 | pmid = 36010971 | pmc = 9406077 | doi = 10.3390/cancers14163976 | doi-access = free }} [173] => [174] => Another role for miRNA in cancers is to use their expression level for prognosis. In [[non-small-cell lung carcinoma|NSCLC]] samples, low [[MiR-324-5p|miR-324]]a levels may serve as an indicator of poor survival.{{cite journal | vauthors = Võsa U, Vooder T, Kolde R, Fischer K, Välk K, Tõnisson N, Roosipuu R, Vilo J, Metspalu A, Annilo T | title = Identification of miR-374a as a prognostic marker for survival in patients with early-stage nonsmall cell lung cancer | journal = Genes, Chromosomes & Cancer | volume = 50 | issue = 10 | pages = 812–22 | date = October 2011 | pmid = 21748820 | doi = 10.1002/gcc.20902 | s2cid = 9746594 | url = https://zenodo.org/record/1119590 }} Either high miR-185 or low miR-133b levels may correlate with [[metastasis]] and poor survival in [[colorectal cancer]].{{cite journal | vauthors = Akçakaya P, Ekelund S, Kolosenko I, Caramuta S, Ozata DM, Xie H, Lindforss U, Olivecrona H, Lui WO | title = miR-185 and miR-133b deregulation is associated with overall survival and metastasis in colorectal cancer | journal = International Journal of Oncology | volume = 39 | issue = 2 | pages = 311–8 | date = August 2011 | pmid = 21573504 | doi = 10.3892/ijo.2011.1043 | doi-access = free }} [175] => [176] => Furthermore, specific miRNAs may be associated with certain histological subtypes of colorectal cancer. For instance, expression levels of miR-205 and miR-373 have been shown to be increased in mucinous colorectal cancers and mucin-producing Ulcerative Colitis-associated colon cancers, but not in sporadic colonic adenocarcinoma that lack mucinous components.{{cite journal | vauthors = Eyking A, Reis H, Frank M, Gerken G, Schmid KW, Cario E | title = MiR-205 and MiR-373 Are Associated with Aggressive Human Mucinous Colorectal Cancer | journal = PLOS ONE | volume = 11 | issue = 6 | pages = e0156871 | year = 2016 | pmid = 27271572 | pmc = 4894642 | doi = 10.1371/journal.pone.0156871 | bibcode = 2016PLoSO..1156871E | doi-access = free }} In-vitro studies suggested that miR-205 and miR-373 may functionally induce different features of mucinous-associated neoplastic progression in intestinal epithelial cells. [177] => [178] => Hepatocellular carcinoma cell proliferation may arise from miR-21 interaction with MAP2K3, a tumor repressor gene.MicroRNA-21 promotes hepatocellular carcinoma HepG2 cell proliferation through repression of mitogen-activated protein kinase-kinase 3. Guangxian Xu et al., 2013 Optimal treatment for cancer involves accurately identifying patients for risk-stratified therapy. Those with a rapid response to initial treatment may benefit from truncated treatment regimens, showing the value of accurate disease response measures. Cell-free circulating miRNAs (cimiRNAs) are highly stable in blood, are overexpressed in cancer and are quantifiable within the diagnostic laboratory. In classical [[Hodgkin lymphoma]], plasma miR-21, miR-494, and miR-1973 are promising disease response biomarkers.{{cite journal | vauthors = Jones K, Nourse JP, Keane C, Bhatnagar A, Gandhi MK | title = Plasma microRNA are disease response biomarkers in classical Hodgkin lymphoma | journal = Clinical Cancer Research | volume = 20 | issue = 1 | pages = 253–64 | date = January 2014 | pmid = 24222179 | doi = 10.1158/1078-0432.CCR-13-1024 | doi-access = free }} Circulating miRNAs have the potential to assist clinical decision making and aid interpretation of [[positron emission tomography]] combined with [[computerized tomography]]. They can be performed at each consultation to assess disease response and detect relapse. [179] => [180] => MicroRNAs have the potential to be used as tools or targets for treatment of different cancers.{{cite journal | vauthors = Hosseinahli N, Aghapour M, Duijf PH, Baradaran B | title = Treating cancer with microRNA replacement therapy: A literature review | journal = Journal of Cellular Physiology | volume = 233 | issue = 8 | pages = 5574–5588 | date = August 2018 | pmid = 29521426 | doi = 10.1002/jcp.26514 | s2cid = 3766576 | doi-access = free }} The specific microRNA, miR-506 has been found to work as a tumor antagonist in several studies. A significant number of cervical cancer samples were found to have downregulated expression of miR-506. Additionally, miR-506 works to promote apoptosis of cervical cancer cells, through its direct target hedgehog pathway transcription factor, Gli3.{{cite journal | vauthors = Liu G, Sun Y, Ji P, Li X, Cogdell D, Yang D, Parker Kerrigan BC, Shmulevich I, Chen K, Sood AK, Xue F, Zhang W | title = MiR-506 suppresses proliferation and induces senescence by directly targeting the CDK4/6-FOXM1 axis in ovarian cancer | journal = The Journal of Pathology | volume = 233 | issue = 3 | pages = 308–18 | date = July 2014 | pmid = 24604117 | pmc = 4144705 | doi = 10.1002/path.4348 }}{{cite journal | vauthors = Wen SY, Lin Y, Yu YQ, Cao SJ, Zhang R, Yang XM, Li J, Zhang YL, Wang YH, Ma MZ, Sun WW, Lou XL, Wang JH, Teng YC, Zhang ZG | title = miR-506 acts as a tumor suppressor by directly targeting the hedgehog pathway transcription factor Gli3 in human cervical cancer | journal = Oncogene | volume = 34 | issue = 6 | pages = 717–25 | date = February 2015 | pmid = 24608427 | doi = 10.1038/onc.2014.9 | s2cid = 20603801 | doi-access = free }} [181] => [182] => ===DNA repair and cancer=== [183] => Many miRNAs can directly target and inhibit [[cell cycle]] genes to control [[cell proliferation]]. A new strategy for tumor treatment is to inhibit tumor cell proliferation by repairing the defective miRNA pathway in tumors.{{cite journal|url= [184] => https://scitechdaily.com/scientists-develop-a-new-powerful-cancer-fighting-weapon/amp/|title=Scientists Develop a New, Powerful Cancer-Fighting Weapon|date=September 13, 2022|access-date=September 15, 2022|author=[[Peking University]]|journal=Cell |volume=185 |issue=11 |pages=1888–1904.e24 |publisher=[[SciTech (magazine)|SciTech Daily]]|doi=10.1016/j.cell.2022.04.030|pmid=35623329 |s2cid=249070106 |doi-access=free}} [185] => Cancer is caused by the accumulation of [[mutation]]s from either DNA damage or uncorrected errors in [[DNA replication]].{{cite journal | vauthors = Loeb KR, Loeb LA | title = Significance of multiple mutations in cancer | journal = Carcinogenesis | volume = 21 | issue = 3 | pages = 379–385 | date = March 2000 | pmid = 10688858 | doi = 10.1093/carcin/21.3.379 | doi-access = free }} Defects in [[DNA repair]] cause the accumulation of mutations, which can lead to cancer.{{cite book | vauthors = Lodish H, Berk A, Kaiser CA, Krieger M, Bretscher A, Ploegh H, Amon A, Martin KC |title=Molecular Cell Biology |date=2016 |publisher=W. H. Freeman and Company |location=New York |isbn=978-1-4641-8339-3 |page=203 |edition=8th}} Several genes involved in DNA repair are regulated by microRNAs.{{cite journal | vauthors = Hu H, Gatti RA | title = MicroRNAs: new players in the DNA damage response | journal = Journal of Molecular Cell Biology | volume = 3 | issue = 3 | pages = 151–158 | date = June 2011 | pmid = 21183529 | pmc = 3104011 | doi = 10.1093/jmcb/mjq042 }} [186] => [187] => [[Germline]] mutations in DNA repair genes cause only 2–5% of [[colon cancer]] cases.{{cite journal | vauthors = Jasperson KW, Tuohy TM, Neklason DW, Burt RW | title = Hereditary and familial colon cancer | journal = Gastroenterology | volume = 138 | issue = 6 | pages = 2044–58 | date = June 2010 | pmid = 20420945 | pmc = 3057468 | doi = 10.1053/j.gastro.2010.01.054 }} However, altered expression of microRNAs, causing DNA repair deficiencies, are frequently associated with cancers and may be an important [[causality|causal]] factor. Among 68 sporadic colon cancers with reduced expression of the [[DNA mismatch repair]] protein [[MLH1]], most were found to be deficient due to [[epigenetic methylation]] of the [[CpG site|CpG]] island of the [[MLH1]] gene.{{cite journal | vauthors = Truninger K, Menigatti M, Luz J, Russell A, Haider R, Gebbers JO, Bannwart F, Yurtsever H, Neuweiler J, Riehle HM, Cattaruzza MS, Heinimann K, Schär P, Jiricny J, Marra G | title = Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer | journal = Gastroenterology | volume = 128 | issue = 5 | pages = 1160–71 | date = May 2005 | pmid = 15887099 | doi = 10.1053/j.gastro.2005.01.056 | doi-access = free }} However, up to 15% of MLH1-deficiencies in sporadic colon cancers appeared to be due to over-expression of the microRNA miR-155, which represses MLH1 expression.{{cite journal | vauthors = Valeri N, Gasparini P, Fabbri M, Braconi C, Veronese A, Lovat F, Adair B, Vannini I, Fanini F, Bottoni A, Costinean S, Sandhu SK, Nuovo GJ, Alder H, Gafa R, Calore F, Ferracin M, Lanza G, Volinia S, Negrini M, McIlhatton MA, Amadori D, Fishel R, Croce CM | title = Modulation of mismatch repair and genomic stability by miR-155 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 15 | pages = 6982–7 | date = April 2010 | pmid = 20351277 | pmc = 2872463 | doi = 10.1073/pnas.1002472107 | bibcode = 2010PNAS..107.6982V | doi-access = free }} [188] => [189] => In 29–66%{{cite journal | vauthors = Zhang W, Zhang J, Hoadley K, Kushwaha D, Ramakrishnan V, Li S, Kang C, You Y, Jiang C, Song SW, Jiang T, Chen CC | title = miR-181d: a predictive glioblastoma biomarker that downregulates MGMT expression | journal = Neuro-Oncology | volume = 14 | issue = 6 | pages = 712–9 | date = June 2012 | pmid = 22570426 | pmc = 3367855 | doi = 10.1093/neuonc/nos089 }}{{cite journal | vauthors = Spiegl-Kreinecker S, Pirker C, Filipits M, Lötsch D, Buchroithner J, Pichler J, Silye R, Weis S, Micksche M, Fischer J, Berger W | title = O6-Methylguanine DNA methyltransferase protein expression in tumor cells predicts outcome of temozolomide therapy in glioblastoma patients | journal = Neuro-Oncology | volume = 12 | issue = 1 | pages = 28–36 | date = January 2010 | pmid = 20150365 | pmc = 2940563 | doi = 10.1093/neuonc/nop003 }} of [[glioblastomas]], DNA repair is deficient due to epigenetic methylation of the [[O-6-methylguanine-DNA methyltransferase|MGMT]] gene, which reduces protein expression of MGMT. However, for 28% of glioblastomas, the MGMT protein is deficient, but the MGMT promoter is not methylated. In glioblastomas without methylated MGMT promoters, the level of microRNA miR-181d is [[inversely correlated]] with protein expression of MGMT and the direct target of miR-181d is the MGMT [[mRNA]] 3'UTR (the [[three prime untranslated region]] of MGMT mRNA). Thus, in 28% of glioblastomas, increased expression of miR-181d and reduced expression of DNA repair enzyme MGMT may be a causal factor. [190] => [191] => [[HMGA]] proteins (HMGA1a, HMGA1b and HMGA2) are implicated in cancer, and expression of these proteins is regulated by microRNAs. HMGA expression is almost undetectable in differentiated adult tissues, but is elevated in many cancers. HMGA proteins are [[polypeptides]] of ~100 amino acid residues characterized by a modular sequence organization. These proteins have three highly positively charged regions, termed [[AT hook]]s, that bind the minor groove of AT-rich DNA stretches in specific regions of DNA. Human neoplasias, including thyroid, prostatic, cervical, colorectal, pancreatic and ovarian carcinomas, show a strong increase of HMGA1a and HMGA1b proteins.{{cite journal | vauthors = Sgarra R, Rustighi A, Tessari MA, Di Bernardo J, Altamura S, Fusco A, Manfioletti G, Giancotti V | title = Nuclear phosphoproteins HMGA and their relationship with chromatin structure and cancer | journal = FEBS Letters | volume = 574 | issue = 1–3 | pages = 1–8 | date = September 2004 | pmid = 15358530 | doi = 10.1016/j.febslet.2004.08.013 | s2cid = 28903539 }} Transgenic mice with HMGA1 targeted to lymphoid cells develop aggressive lymphoma, showing that high HMGA1 expression is associated with cancers and that HMGA1 can act as an oncogene.{{cite journal | vauthors = Xu Y, Sumter TF, Bhattacharya R, Tesfaye A, Fuchs EJ, Wood LJ, Huso DL, Resar LM | title = The HMG-I oncogene causes highly penetrant, aggressive lymphoid malignancy in transgenic mice and is overexpressed in human leukemia | journal = Cancer Research | volume = 64 | issue = 10 | pages = 3371–5 | date = May 2004 | pmid = 15150086 | doi = 10.1158/0008-5472.CAN-04-0044 | doi-access = free }} HMGA2 protein specifically targets the promoter of [[ERCC1]], thus reducing expression of this DNA repair gene.{{cite journal | vauthors = Borrmann L, Schwanbeck R, Heyduk T, Seebeck B, Rogalla P, Bullerdiek J, Wisniewski JR | title = High mobility group A2 protein and its derivatives bind a specific region of the promoter of DNA repair gene ERCC1 and modulate its activity | journal = Nucleic Acids Research | volume = 31 | issue = 23 | pages = 6841–51 | date = December 2003 | pmid = 14627817 | pmc = 290254 | doi = 10.1093/nar/gkg884 }} ERCC1 protein expression was deficient in 100% of 47 evaluated colon cancers (though the extent to which HGMA2 was involved is not known).{{cite journal | vauthors = Facista A, Nguyen H, Lewis C, Prasad AR, Ramsey L, Zaitlin B, Nfonsam V, Krouse RS, Bernstein H, Payne CM, Stern S, Oatman N, Banerjee B, Bernstein C | title = Deficient expression of DNA repair enzymes in early progression to sporadic colon cancer | journal = Genome Integrity | volume = 3 | issue = 1 | pages = 3 | date = April 2012 | pmid = 22494821 | pmc = 3351028 | doi = 10.1186/2041-9414-3-3 | doi-access = free }} [192] => [193] => Single Nucleotide polymorphisms (SNPs) can alter the binding of miRNAs on 3'UTRs for example the case of hsa-mir181a and hsa-mir181b on the CDON tumor suppressor gene.{{cite journal | vauthors = Gibert B, Delloye-Bourgeois C, Gattolliat CH, Meurette O, Le Guernevel S, Fombonne J, Ducarouge B, Lavial F, Bouhallier F, Creveaux M, Negulescu AM, Bénard J, Janoueix-Lerosey I, Harel-Bellan A, Delattre O, Mehlen P | title = Regulation by miR181 family of the dependence receptor CDON tumor suppressive activity in neuroblastoma | journal = Journal of the National Cancer Institute | volume = 106 | issue = 11 | date = November 2014 | pmid = 25313246 | doi = 10.1093/jnci/dju318 | doi-access = free }} [194] => [195] => ===Heart disease=== [196] => The global role of miRNA function in the heart has been addressed by conditionally inhibiting miRNA maturation in the [[Laboratory mouse|murine]] heart. This revealed that miRNAs play an essential role during its development.{{cite journal | vauthors = Chen JF, Murchison EP, Tang R, Callis TE, Tatsuguchi M, Deng Z, Rojas M, Hammond SM, Schneider MD, Selzman CH, Meissner G, Patterson C, Hannon GJ, Wang DZ |author-link2=Elizabeth Murchison|author-link13=Gregory Hannon| title = Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 6 | pages = 2111–6 | date = February 2008 | pmid = 18256189 | pmc = 2542870 | doi = 10.1073/pnas.0710228105 | bibcode = 2008PNAS..105.2111C |doi-access=free}}{{cite journal | vauthors = Zhao Y, Ransom JF, Li A, Vedantham V, von Drehle M, Muth AN, Tsuchihashi T, McManus MT, Schwartz RJ, Srivastava D | title = Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2 | journal = Cell | volume = 129 | issue = 2 | pages = 303–17 | date = April 2007 | pmid = 17397913 | doi = 10.1016/j.cell.2007.03.030 | doi-access = free }} miRNA expression profiling studies demonstrate that expression levels of specific miRNAs change in diseased human hearts, pointing to their involvement in [[Cardiomyopathy|cardiomyopathies]].{{cite journal | vauthors = Thum T, Galuppo P, Wolf C, Fiedler J, Kneitz S, van Laake LW, Doevendans PA, Mummery CL, Borlak J, Haverich A, Gross C, Engelhardt S, Ertl G, Bauersachs J | title = MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure | journal = Circulation | volume = 116 | issue = 3 | pages = 258–67 | date = July 2007 | pmid = 17606841 | doi = 10.1161/CIRCULATIONAHA.107.687947 | doi-access = free }}{{cite journal | vauthors = van Rooij E, Sutherland LB, Liu N, Williams AH, McAnally J, Gerard RD, Richardson JA, Olson EN | title = A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 48 | pages = 18255–60 | date = November 2006 | pmid = 17108080 | pmc = 1838739 | doi = 10.1073/pnas.0608791103 | bibcode = 2006PNAS..10318255V | doi-access = free }}{{cite journal | vauthors = Tatsuguchi M, Seok HY, Callis TE, Thomson JM, Chen JF, Newman M, Rojas M, Hammond SM, Wang DZ | title = Expression of microRNAs is dynamically regulated during cardiomyocyte hypertrophy | journal = Journal of Molecular and Cellular Cardiology | volume = 42 | issue = 6 | pages = 1137–41 | date = June 2007 | pmid = 17498736 | pmc = 1934409 | doi = 10.1016/j.yjmcc.2007.04.004 }} Furthermore, animal studies on specific miRNAs identified distinct roles for miRNAs both during heart development and under pathological conditions, including the regulation of key factors important for cardiogenesis, the hypertrophic growth response and cardiac conductance.{{cite journal | vauthors = Zhao Y, Samal E, Srivastava D | title = Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis | journal = Nature | volume = 436 | issue = 7048 | pages = 214–20 | date = July 2005 | pmid = 15951802 | doi = 10.1038/nature03817 | bibcode = 2005Natur.436..214Z | s2cid = 4340449 }}{{cite journal | vauthors = Xiao J, Luo X, Lin H, Zhang Y, Lu Y, Wang N, Zhang Y, Yang B, Wang Z | title = MicroRNA miR-133 represses HERG K+ channel expression contributing to QT prolongation in diabetic hearts | journal = The Journal of Biological Chemistry | volume = 282 | issue = 17 | pages = 12363–7 | date = April 2007 | pmid = 17344217 | doi = 10.1074/jbc.C700015200 | doi-access = free | pmc = 3151106 }}{{cite journal | vauthors = Yang B, Lin H, Xiao J, Lu Y, Luo X, Li B, Zhang Y, Xu C, Bai Y, Wang H, Chen G, Wang Z | title = The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2 | journal = Nature Medicine | volume = 13 | issue = 4 | pages = 486–91 | date = April 2007 | pmid = 17401374 | doi = 10.1038/nm1569 | s2cid = 1935811 }}{{cite journal | vauthors = Carè A, Catalucci D, Felicetti F, Bonci D, Addario A, Gallo P, Bang ML, Segnalini P, Gu Y, Dalton ND, Elia L, Latronico MV, Høydal M, Autore C, Russo MA, Dorn GW, Ellingsen O, Ruiz-Lozano P, Peterson KL, Croce CM, Peschle C, Condorelli G | title = MicroRNA-133 controls cardiac hypertrophy | journal = Nature Medicine | volume = 13 | issue = 5 | pages = 613–8 | date = May 2007 | pmid = 17468766 | doi = 10.1038/nm1582 | s2cid = 10097893 }}{{cite journal | vauthors = van Rooij E, Sutherland LB, Qi X, Richardson JA, Hill J, Olson EN | title = Control of stress-dependent cardiac growth and gene expression by a microRNA | journal = Science | volume = 316 | issue = 5824 | pages = 575–9 | date = April 2007 | pmid = 17379774 | doi = 10.1126/science.1139089 | bibcode = 2007Sci...316..575V | s2cid = 1927839 }} Another role for miRNA in cardiovascular diseases is to use their expression levels for diagnosis, prognosis or risk stratification.{{cite journal | vauthors = Keller T, Boeckel JN, Groß S, Klotsche J, Palapies L, Leistner D, Pieper L, Stalla GK, Lehnert H, Silber S, Pittrow D, Maerz W, Dörr M, Wittchen HU, Baumeister SE, Völker U, Felix SB, Dimmeler S, Zeiher AM | title = Improved risk stratification in prevention by use of a panel of selected circulating microRNAs | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 4511 | date = July 2017 | pmid = 28674420 | pmc = 5495799 | doi = 10.1038/s41598-017-04040-w | bibcode = 2017NatSR...7.4511K }} miRNA's in animal models have also been linked to cholesterol metabolism and regulation. [197] => [198] => ====miRNA-712==== [199] => [200] => [[Murine]] microRNA-712 is a potential biomarker (i.e. predictor) for [[atherosclerosis]], a cardiovascular disease of the arterial wall associated with lipid retention and inflammation.{{cite journal | vauthors = Insull W | title = The pathology of atherosclerosis: plaque development and plaque responses to medical treatment | journal = The American Journal of Medicine | volume = 122 | issue = 1 Suppl | pages = S3–S14 | date = January 2009 | pmid = 19110086 | doi = 10.1016/j.amjmed.2008.10.013 }} Non-laminar blood flow also correlates with development of atherosclerosis as mechanosenors of endothelial cells respond to the shear force of disturbed flow (d-flow).{{cite journal | vauthors = Son DJ, Kumar S, Takabe W, Kim CW, Ni CW, Alberts-Grill N, Jang IH, Kim S, Kim W, Won Kang S, Baker AH, Woong Seo J, Ferrara KW, Jo H | title = The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis | journal = Nature Communications | volume = 4 | pages = 3000 | year = 2013 | pmid = 24346612 | pmc = 3923891 | doi = 10.1038/ncomms4000 | bibcode = 2013NatCo...4.3000S }} A number of pro-atherogenic genes including [[matrix metalloproteinase]]s (MMPs) are upregulated by d-flow, mediating pro-inflammatory and pro-angiogenic signals. These findings were observed in ligated carotid arteries of mice to mimic the effects of d-flow. Within 24 hours, pre-existing immature miR-712 formed mature miR-712 suggesting that miR-712 is flow-sensitive. Coinciding with these results, miR-712 is also upregulated in endothelial cells exposed to naturally occurring d-flow in the greater curvature of the aortic arch. [201] => [202] => ====Origin==== [203] => [204] => Pre-mRNA sequence of miR-712 is generated from the murine ribosomal RN45s gene at the [[internal transcribed spacer]] region 2 (ITS2). XRN1 is an exonuclease that degrades the ITS2 region during processing of RN45s. Reduction of XRN1 under d-flow'' ''conditions therefore leads to the accumulation of miR-712. [205] => [206] => ====Mechanism==== [207] => [208] => MiR-712 targets tissue inhibitor of [[Metalloproteinase|metalloproteinases 3]] (TIMP3). TIMPs normally regulate activity of matrix metalloproteinases (MMPs) which degrade the extracellular matrix (ECM). Arterial ECM is mainly composed of [[collagen]] and [[elastin]] fibers, providing the structural support and recoil properties of arteries.{{cite journal | vauthors = Basu R, Fan D, Kandalam V, Lee J, Das SK, Wang X, Baldwin TA, Oudit GY, Kassiri Z | title = Loss of Timp3 gene leads to abdominal aortic aneurysm formation in response to angiotensin II | journal = The Journal of Biological Chemistry | volume = 287 | issue = 53 | pages = 44083–96 | date = December 2012 | pmid = 23144462 | pmc = 3531724 | doi = 10.1074/jbc.M112.425652 | doi-access = free }} These fibers play a critical role in regulation of vascular inflammation and permeability, which are important in the development of atherosclerosis.{{cite journal | vauthors = Libby P | title = Inflammation in atherosclerosis | journal = Nature | volume = 420 | issue = 6917 | pages = 868–74 | year = 2002 | pmid = 12490960 | doi = 10.1038/nature01323 | bibcode = 2002Natur.420..868L | s2cid = 407449 }} Expressed by endothelial cells, TIMP3 is the only ECM-bound TIMP. A decrease in TIMP3 expression results in an increase of ECM degradation in the presence of d-flow. Consistent with these findings, inhibition of pre-miR712 increases expression of TIMP3 in cells, even when exposed to turbulent flow. [209] => [210] => TIMP3 also decreases the expression of TNFα (a pro-inflammatory regulator) during turbulent flow.  Activity of TNFα in turbulent flow was measured by the expression of TNFα-converting enzyme (TACE) in blood. TNFα decreased if miR-712 was inhibited or TIMP3 overexpressed, suggesting that miR-712 and TIMP3 regulate TACE activity in turbulent flow conditions. [211] => [212] => Anti-miR-712 effectively suppresses d-flow-induced miR-712 expression and increases TIMP3 expression. Anti-miR-712 also inhibits vascular hyperpermeability, thereby significantly reducing atherosclerosis lesion development and immune cell infiltration. [213] => [214] => ====Human homolog microRNA-205==== [215] => [216] => The human homolog of miR-712 was found on the RN45s homolog gene, which maintains similar miRNAs to mice. MiR-205 of humans share similar sequences with miR-712 of mice and is conserved across most vertebrates. MiR-205 and miR-712 also share more than 50% of the cell signaling targets, including TIMP3. [217] => [218] => When tested, d-flow decreased the expression of XRN1 in humans as it did in mice endothelial cells, indicating a potentially common role of XRN1 in humans. [219] => [220] => ===Kidney disease=== [221] => Targeted deletion of Dicer in the [[FOXD1|FoxD1]]-derived renal progenitor cells in a murine model resulted in a complex renal phenotype including expansion of [[Nephrology|nephron]] progenitors, fewer [[renin]] cells, smooth muscle [[arteriole]]s, progressive [[Mesangium|mesangial]] loss and glomerular aneurysms.{{cite journal | vauthors = Phua YL, Chu JY, Marrone AK, Bodnar AJ, Sims-Lucas S, Ho J | title = Renal stromal miRNAs are required for normal nephrogenesis and glomerular mesangial survival | journal = Physiological Reports | volume = 3 | issue = 10 | pages = e12537 | date = October 2015 | pmid = 26438731 | pmc = 4632944 | doi = 10.14814/phy2.12537 }} High throughput whole [[transcriptome]] profiling of the FoxD1-Dicer knockout mouse model revealed ectopic upregulation of pro-apoptotic gene, [[BCL2-like 1 (gene)|Bcl2L11]] (Bim) and dysregulation of the [[p53]] pathway with increase in p53 effector genes including [[Bcl-2-associated X protein|Bax]], [[TP53INP1|Trp53inp1]], Jun, [[P21|Cdkn1a]], [[MMP2|Mmp2]], and [[ARID3A|Arid3a]]. p53 protein levels remained unchanged, suggesting that FoxD1 stromal miRNAs directly repress p53-effector genes. Using a lineage tracing approach followed by [[Fluorescent-activated cell sorting]], miRNA profiling of the FoxD1-derived cells not only comprehensively defined the transcriptional landscape of miRNAs that are critical for vascular development, but also identified key miRNAs that are likely to modulate the renal phenotype in its absence. These miRNAs include miRs‐10a, 18a, 19b, 24, 30c, 92a, 106a, 130a, 152, 181a, 214, 222, 302a, 370, and 381 that regulate Bcl2L11 (Bim) and miRs‐15b, 18a, 21, 30c, 92a, 106a, 125b‐5p, 145, 214, 222, 296‐5p and 302a that regulate p53-effector genes. Consistent with the profiling results, ectopic [[apoptosis]] was observed in the cellular derivatives of the FoxD1 derived progenitor lineage and reiterates the importance of renal stromal miRNAs in cellular homeostasis. [222] => [223] => ===Nervous system=== [224] => MiRNAs are crucial for the healthy development and function of the [[nervous system]].{{cite journal | vauthors = Cao DD, Li L, Chan WY | title = MicroRNAs: Key Regulators in the Central Nervous System and Their Implication in Neurological Diseases | journal = International Journal of Molecular Sciences | volume = 17 | issue = 6 | pages = 842 | date = May 2016 | pmid = 27240359 | pmc = 4926376 | doi = 10.3390/ijms17060842 | doi-access = free }} Previous studies demonstrate that miRNAs can regulate neuronal differentiation and maturation at various stages.{{cite journal | vauthors = Lang MF, Shi Y | title = Dynamic Roles of microRNAs in Neurogenesis | journal = Frontiers in Neuroscience | volume = 6 | pages = 71 | date = 2012 | pmid = 22661924 | pmc = 3356852 | doi = 10.3389/fnins.2012.00071 | doi-access = free }} MiRNAs also play important roles in [[Synaptogenesis|synaptic development]]{{cite journal | vauthors = Schratt G | title = microRNAs at the synapse | journal = Nature Reviews. Neuroscience | volume = 10 | issue = 12 | pages = 842–849 | date = December 2009 | pmid = 19888283 | doi = 10.1038/nrn2763 | s2cid = 3507952 }} (such as dendritogenesis or spine morphogenesis) and [[synaptic plasticity]]{{cite journal | vauthors = Luo M, Li L, Ding M, Niu Y, Xu X, Shi X, Shan N, Qiu Z, Piao F, Zhang C | title = Long-term potentiation and depression regulatory microRNAs were highlighted in Bisphenol A induced learning and memory impairment by microRNA sequencing and bioinformatics analysis | journal = PLOS ONE | volume = 18 | issue = 1 | pages = e0279029 | date = 2023-01-19 | pmid = 36656826 | pmc = 9851566 | doi = 10.1371/journal.pone.0279029 | doi-access = free | bibcode = 2023PLoSO..1879029L }} (contributing to learning and memory). Elimination of miRNA formation in mice by experimental silencing of [[Dicer]] has led to pathological outcomes, such as reduced neuronal size, motor abnormalities (when silenced in [[striatum|striatal]] neurons{{cite journal | vauthors = Cuellar TL, Davis TH, Nelson PT, Loeb GB, Harfe BD, Ullian E, McManus MT | title = Dicer loss in striatal neurons produces behavioral and neuroanatomical phenotypes in the absence of neurodegeneration | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 14 | pages = 5614–5619 | date = April 2008 | pmid = 18385371 | pmc = 2291142 | doi = 10.1073/pnas.0801689105 | doi-access = free | bibcode = 2008PNAS..105.5614C }}), and neurodegeneration (when silenced in [[forebrain]] neurons{{cite journal | vauthors = Hébert SS, Papadopoulou AS, Smith P, Galas MC, Planel E, Silahtaroglu AN, Sergeant N, Buée L, De Strooper B | title = Genetic ablation of Dicer in adult forebrain neurons results in abnormal tau hyperphosphorylation and neurodegeneration | journal = Human Molecular Genetics | volume = 19 | issue = 20 | pages = 3959–3969 | date = October 2010 | pmid = 20660113 | doi = 10.1093/hmg/ddq311 | doi-access = free }}). Altered miRNA expression has been found in neurodegenerative diseases (such as [[Alzheimer's disease]], [[Parkinson's disease]], and [[Huntington's disease]]{{cite journal | vauthors = Roy B, Lee E, Li T, Rampersaud M | title = Role of miRNAs in Neurodegeneration: From Disease Cause to Tools of Biomarker Discovery and Therapeutics | journal = Genes | volume = 13 | issue = 3 | pages = 425 | date = February 2022 | pmid = 35327979 | pmc = 8951370 | doi = 10.3390/genes13030425 | doi-access = free }}) as well as many psychiatric disorders (including [[epilepsy]],{{cite journal | vauthors = Henshall DC, Hamer HM, Pasterkamp RJ, Goldstein DB, Kjems J, Prehn JH, Schorge S, Lamottke K, Rosenow F | title = MicroRNAs in epilepsy: pathophysiology and clinical utility | journal = The Lancet. Neurology | volume = 15 | issue = 13 | pages = 1368–1376 | date = December 2016 | pmid = 27839653 | doi = 10.1016/S1474-4422(16)30246-0 | doi-access = free }} [[schizophrenia]], [[major depressive disorder|major depression]], [[bipolar disorder]], and [[anxiety disorder]]s{{cite journal | vauthors = Hommers LG, Domschke K, Deckert J | title = Heterogeneity and individuality: microRNAs in mental disorders | journal = Journal of Neural Transmission | volume = 122 | issue = 1 | pages = 79–97 | date = January 2015 | pmid = 25395183 | doi = 10.1007/s00702-014-1338-4 | url = https://www.molekulartherapie.de/resources/Hommers_Heterogeneity+Individuality.pdf | url-status = live | s2cid-access = free | s2cid = 25088900 | archive-url = https://web.archive.org/web/20220523074509/https://molekulartherapie.de/resources/Hommers_Heterogeneity+Individuality.pdf | archive-date = May 23, 2022 }}{{cite journal | vauthors = Feng J, Sun G, Yan J, Noltner K, Li W, Buzin CH, Longmate J, Heston LL, Rossi J, Sommer SS | title = Evidence for X-chromosomal schizophrenia associated with microRNA alterations | journal = PLOS ONE | volume = 4 | issue = 7 | pages = e6121 | date = July 2009 | pmid = 19568434 | pmc = 2699475 | doi = 10.1371/journal.pone.0006121 | veditors = Reif A | bibcode-access = free | doi-access = free | bibcode = 2009PLoSO...4.6121F }}{{cite journal | vauthors = Beveridge NJ, Gardiner E, Carroll AP, Tooney PA, Cairns MJ | title = Schizophrenia is associated with an increase in cortical microRNA biogenesis | journal = Molecular Psychiatry | volume = 15 | issue = 12 | pages = 1176–1189 | date = December 2010 | pmid = 19721432 | pmc = 2990188 | doi = 10.1038/mp.2009.84 | doi-access = free }}). [225] => [226] => ====Stroke==== [227] => According to the Center for Disease Control and Prevention, Stroke is one of the leading causes of death and long-term disability in America. 87% of the cases are [[Ischemic stroke|ischemic strokes]], which results from blockage in the artery of the brain that carries oxygen-rich blood. The obstruction of the blood flow means the brain cannot receive necessary nutrients, such as oxygen and glucose, and remove wastes, such as carbon dioxide.{{Cite web|url=https://www.cdc.gov/stroke/facts.htm|title=Stroke Facts |date=2019-03-15|website=Centers for Disease Control and Prevention |language=en-us|access-date=2019-12-05}}{{cite journal | vauthors = Rink C, Khanna S | title = MicroRNA in ischemic stroke etiology and pathology | journal = Physiological Genomics | volume = 43 | issue = 10 | pages = 521–528 | date = May 2011 | pmid = 20841499 | pmc = 3110894 | doi = 10.1152/physiolgenomics.00158.2010 }} miRNAs plays a role in posttranslational gene silencing by targeting genes in the pathogenesis of cerebral ischemia, such as the inflammatory, angiogenesis, and apoptotic pathway.{{cite journal | vauthors = Ouyang YB, Stary CM, Yang GY, Giffard R | title = microRNAs: innovative targets for cerebral ischemia and stroke | journal = Current Drug Targets | volume = 14 | issue = 1 | pages = 90–101 | date = January 2013 | pmid = 23170800 | pmc = 3673881 | doi = 10.2174/138945013804806424 }}  [228] => [229] => ====Alcoholism==== [230] => The vital role of miRNAs in gene expression is significant to [[addiction]], specifically [[alcoholism]].{{cite journal | vauthors = Lewohl JM, Nunez YO, Dodd PR, Tiwari GR, Harris RA, Mayfield RD | title = Up-regulation of microRNAs in brain of human alcoholics | journal = Alcoholism: Clinical and Experimental Research | volume = 35 | issue = 11 | pages = 1928–37 | date = November 2011 | pmid = 21651580 | pmc = 3170679 | doi = 10.1111/j.1530-0277.2011.01544.x }} Chronic alcohol abuse results in persistent changes in brain function mediated in part by alterations in [[gene expression]]. miRNA global regulation of many downstream genes deems significant regarding the reorganization or synaptic connections or long term neural adaptations involving the behavioral change from alcohol consumption to [[alcohol withdrawal syndrome|withdrawal]] and/or dependence.{{cite journal | vauthors = Tapocik JD, Solomon M, Flanigan M, Meinhardt M, Barbier E, Schank JR, Schwandt M, Sommer WH, Heilig M | title = Coordinated dysregulation of mRNAs and microRNAs in the rat medial prefrontal cortex following a history of alcohol dependence | journal = The Pharmacogenomics Journal | volume = 13 | issue = 3 | pages = 286–96 | date = June 2013 | pmid = 22614244 | pmc = 3546132 | doi = 10.1038/tpj.2012.17 }} Up to 35 different miRNAs have been found to be altered in the alcoholic post-mortem brain, all of which target genes that include the regulation of the [[cell cycle]], [[apoptosis]], [[cell adhesion]], [[neural development|nervous system development]] and [[cell signaling]]. Altered miRNA levels were found in the medial [[prefrontal cortex]] of alcohol-dependent mice, suggesting the role of miRNA in orchestrating translational imbalances and the creation of differentially expressed proteins within an area of the brain where complex cognitive behavior and [[decision making]] likely originate.{{cite journal | vauthors = Gorini G, Nunez YO, Mayfield RD | title = Integration of miRNA and protein profiling reveals coordinated neuroadaptations in the alcohol-dependent mouse brain | journal = PLOS ONE | volume = 8 | issue = 12 | pages = e82565 | year = 2013 | pmid = 24358208 | pmc = 3865091 | doi = 10.1371/journal.pone.0082565 | bibcode = 2013PLoSO...882565G | doi-access = free }} [231] => [232] => miRNAs can be either upregulated or downregulated in response to chronic alcohol use. [[miR-206]] expression increased in the prefrontal cortex of alcohol-dependent rats, targeting the transcription factor brain-derived neurotrophic factor ([[BDNF]]) and ultimately reducing its expression. BDNF plays a critical role in the formation and maturation of new neurons and synapses, suggesting a possible implication in synapse growth/[[synaptic plasticity]] in alcohol abusers.{{cite journal | vauthors = Tapocik JD, Barbier E, Flanigan M, Solomon M, Pincus A, Pilling A, Sun H, Schank JR, King C, Heilig M | title = microRNA-206 in rat medial prefrontal cortex regulates BDNF expression and alcohol drinking | journal = The Journal of Neuroscience | volume = 34 | issue = 13 | pages = 4581–8 | date = March 2014 | pmid = 24672003 | pmc = 3965783 | doi = 10.1523/JNEUROSCI.0445-14.2014 }} miR-155, important in regulating alcohol-induced [[neuroinflammation]] responses, was found to be upregulated, suggesting the role of [[microglia]] and inflammatory [[cytokine]]s in alcohol pathophysiology.{{cite journal | vauthors = Lippai D, Bala S, Csak T, Kurt-Jones EA, Szabo G | title = Chronic alcohol-induced microRNA-155 contributes to neuroinflammation in a TLR4-dependent manner in mice | journal = PLOS ONE | volume = 8 | issue = 8 | pages = e70945 | year = 2013 | pmid = 23951048 | pmc = 3739772 | doi = 10.1371/journal.pone.0070945 | bibcode = 2013PLoSO...870945L | doi-access = free }} Downregulation of miR-382 was found in the [[nucleus accumbens]], a structure in the [[basal forebrain]] significant in regulating feelings of [[reward system|reward]] that power motivational habits. miR-382 is the target for the [[dopamine receptor D1]] (DRD1), and its overexpression results in the upregulation of DRD1 and delta [[fosB]], a transcription factor that activates a series of transcription events in the nucleus [[accumbens]] that ultimately result in addictive behaviors.{{cite journal | vauthors = Li J, Li J, Liu X, Qin S, Guan Y, Liu Y, Cheng Y, Chen X, Li W, Wang S, Xiong M, Kuzhikandathil EV, Ye JH, Zhang C | title = MicroRNA expression profile and functional analysis reveal that miR-382 is a critical novel gene of alcohol addiction | journal = EMBO Molecular Medicine | volume = 5 | issue = 9 | pages = 1402–14 | date = September 2013 | pmid = 23873704 | pmc = 3799494 | doi = 10.1002/emmm.201201900 }} Alternatively, overexpressing miR-382 resulted in attenuated drinking and the inhibition of [[Dopamine receptor D1|DRD1]] and delta [[fosB]] upregulation in rat models of alcoholism, demonstrating the possibility of using miRNA-targeted [[pharmaceutical drug|pharmaceuticals]] in treatments. [233] => [234] => ===Obesity=== [235] => miRNAs play crucial roles in the regulation of [[stem cell]] progenitors differentiating into [[adipocyte]]s.{{cite journal | vauthors = Romao JM, Jin W, Dodson MV, Hausman GJ, Moore SS, Guan LL | title = MicroRNA regulation in mammalian adipogenesis | journal = Experimental Biology and Medicine | volume = 236 | issue = 9 | pages = 997–1004 | date = September 2011 | pmid = 21844119 | doi = 10.1258/ebm.2011.011101 | s2cid = 30646787 }} Studies to determine what role [[pluripotent stem cells]] play in [[adipogenesis]], were examined in the immortalized human [[bone marrow]]-derived [[stromal cell]] line hMSC-Tert20.{{cite journal | vauthors = Skårn M, Namløs HM, Noordhuis P, Wang MY, Meza-Zepeda LA, Myklebost O | title = Adipocyte differentiation of human bone marrow-derived stromal cells is modulated by microRNA-155, microRNA-221, and microRNA-222 | journal = Stem Cells and Development | volume = 21 | issue = 6 | pages = 873–83 | date = April 2012 | pmid = 21756067 | doi = 10.1089/scd.2010.0503 | hdl = 10852/40423 | hdl-access = free }} Decreased expression of [[miR-155]], [[Mir-221 microRNA|miR-221]], and [[Mir-221 microRNA|miR-222]], have been found during the adipogenic programming of both immortalized and primary hMSCs, suggesting that they act as negative regulators of differentiation. Conversely, [[ectopic expression]] of the miRNAs [[MiR-155|155]], [[Mir-221 microRNA|221]], and [[Mir-221 microRNA|222]] significantly inhibited adipogenesis and repressed induction of the master regulators [[PPARγ]] and CCAAT/enhancer-binding protein alpha ([[CEBPA]]).{{cite journal | vauthors = Zuo Y, Qiang L, Farmer SR | title = Activation of CCAAT/enhancer-binding protein (C/EBP) alpha expression by C/EBP beta during adipogenesis requires a peroxisome proliferator-activated receptor-gamma-associated repression of HDAC1 at the C/ebp alpha gene promoter | journal = The Journal of Biological Chemistry | volume = 281 | issue = 12 | pages = 7960–7 | date = March 2006 | pmid = 16431920 | doi = 10.1074/jbc.M510682200 | doi-access = free }} This paves the way for possible genetic obesity treatments. [236] => [237] => Another class of miRNAs that regulate [[insulin resistance]], [[obesity]], and [[diabetes]], is the [[Let-7 microRNA precursor|let-7]] family. Let-7 accumulates in human tissues during the course of [[aging]].{{cite journal | vauthors = Jun-Hao ET, Gupta RR, Shyh-Chang N | title = Lin28 and let-7 in the Metabolic Physiology of Aging | journal = Trends in Endocrinology and Metabolism | volume = 27 | issue = 3 | pages = 132–141 | date = March 2016 | pmid = 26811207 | doi = 10.1016/j.tem.2015.12.006 | s2cid = 3614126 }} When let-7 was ectopically overexpressed to mimic accelerated aging, mice became insulin-resistant, and thus more prone to high fat diet-induced obesity and [[diabetes]].{{cite journal | vauthors = Zhu H, Shyh-Chang N, Segrè AV, Shinoda G, Shah SP, Einhorn WS, Takeuchi A, Engreitz JM, Hagan JP, Kharas MG, Urbach A, Thornton JE, Triboulet R, Gregory RI, Altshuler D, Daley GQ | title = The Lin28/let-7 axis regulates glucose metabolism | journal = Cell | volume = 147 | issue = 1 | pages = 81–94 | date = September 2011 | pmid = 21962509 | pmc = 3353524 | doi = 10.1016/j.cell.2011.08.033 }} In contrast when let-7 was inhibited by injections of let-7-specific [[antagomir]]s, mice become more insulin-sensitive and remarkably resistant to high fat diet-induced obesity and diabetes. Not only could let-7 inhibition prevent obesity and diabetes, it could also reverse and cure the condition.{{cite journal | vauthors = Frost RJ, Olson EN | title = Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 52 | pages = 21075–80 | date = December 2011 | pmid = 22160727 | pmc = 3248488 | doi = 10.1073/pnas.1118922109 | bibcode = 2011PNAS..10821075F | doi-access = free }} These experimental findings suggest that let-7 inhibition could represent a new therapy for [[obesity]] and type 2 diabetes. [238] => [239] => ===Hemostasis=== [240] => miRNAs also play crucial roles in the regulation of complex enzymatic cascades including the hemostatic blood coagulation system.{{cite journal | vauthors = Teruel-Montoya R, Rosendaal FR, Martínez C | title = MicroRNAs in hemostasis | journal = Journal of Thrombosis and Haemostasis | volume = 13 | issue = 2 | pages = 170–181 | date = February 2015 | pmid = 25400249 | doi = 10.1111/jth.12788 | doi-access = free }} Large scale studies of functional miRNA targeting have recently uncovered rationale therapeutic targets in the hemostatic system.{{cite journal | vauthors = Nourse J, Braun J, Lackner K, Hüttelmaier S, Danckwardt S | title = Large-scale identification of functional microRNA targeting reveals cooperative regulation of the hemostatic system | journal = Journal of Thrombosis and Haemostasis | volume = 16 | issue = 11 | pages = 2233–2245 | date = November 2018 | pmid = 30207063 | doi = 10.1111/jth.14290 | doi-access = free }}{{cite journal | vauthors = Nourse J, Danckwardt S | title = A novel rationale for targeting FXI: Insights from the hemostatic microRNA targetome for emerging anticoagulant strategies | journal = Pharmacology & Therapeutics | volume = 218 | pages = 107676 | date = February 2021 | pmid = 32898547 | doi = 10.1016/j.pharmthera.2020.107676 | doi-access = free }} They have been directly linked to Calcium homeostasis in the endoplasmic reticulum, which is critical in cell differentiation in early development.{{cite journal | vauthors = Berardi E, Pues M, Thorrez L, Sampaolesi M | title = miRNAs in ESC differentiation | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 303 | issue = 8 | pages = H931–H939 | date = October 2012 | doi = 10.1152/ajpheart.00338.2012 | pmid = 22886416 | s2cid = 6402014 }} [241] => [242] => == Plants == [243] => miRNAs are considered to be key regulators of many developmental, homeostatic, and immune processes in plants.{{cite journal | vauthors = Borchers A, Pieler T | title = Programming pluripotent precursor cells derived from Xenopus embryos to generate specific tissues and organs | journal = Genes | volume = 1 | issue = 3 | pages = 413–426 | date = November 2010 | doi = 10.3390/ijms232314755 | pmid = 36499082 | pmc = 9740008 | doi-access = free }} Their roles in plant development include shoot apical meristem development, leaf growth, flower formation, seed production, or root expansion.{{cite journal | vauthors = Curaba J, Spriggs A, Taylor J, Li Z, Helliwell C | title = miRNA regulation in the early development of barley seed | journal = BMC Plant Biology | volume = 12 | issue = 1 | pages = 120 | date = July 2012 | pmid = 22838835 | pmc = 3443071 | doi = 10.1186/1471-2229-12-120 | doi-access = free }}{{Cite journal | vauthors = Choudhary A, Kumar A, Kaur H, Kaur N |date= May 2021 |title=MiRNA: the taskmaster of plant world |journal=Biologia |language=en |volume=76 |issue=5 |pages=1551–1567 |doi=10.1007/s11756-021-00720-1 |bibcode= 2021Biolg..76.1551C |s2cid= 233685660 |issn=1336-9563}}{{cite journal | vauthors = Waheed S, Zeng L | title = The Critical Role of miRNAs in Regulation of Flowering Time and Flower Development | journal = Genes | volume = 11 | issue = 3 | pages = 319 | date = March 2020 | doi = 10.3390/genes11030319 | pmid = 32192095 | pmc = 7140873 | doi-access = free }}{{cite journal | vauthors = Wong CE, Zhao YT, Wang XJ, Croft L, Wang ZH, Haerizadeh F, Mattick JS, Singh MB, Carroll BJ, Bhalla PL | title = MicroRNAs in the shoot apical meristem of soybean | journal = Journal of Experimental Botany | volume = 62 | issue = 8 | pages = 2495–2506 | date = May 2011 | pmid = 21504877 | doi = 10.1093/jxb/erq437 | hdl = 10536/DRO/DU:30106047 | hdl-access = free }} In addition, they play a complex role in responses to various abiotic stresses comprising heat stress, low-temperature stress, drought stress, light stress, or gamma radiation exposure. [244] => [245] => ==Viruses== [246] => Viral microRNAs play an important role in the regulation of gene expression of viral and/or host genes to benefit the virus. Hence, miRNAs play a key role in host–virus interactions and pathogenesis of viral diseases.{{cite journal | vauthors = Qureshi A, Thakur N, Monga I, Thakur A, Kumar M | title = VIRmiRNA: a comprehensive resource for experimentally validated viral miRNAs and their targets | journal = Database | volume = 2014 | pages = bau103 | date = 1 January 2014 | pmid = 25380780 | pmc = 4224276 | doi = 10.1093/database/bau103 }}{{cite web | vauthors = Kumar M |title = VIRmiRNA | website = Resource for experimental viral miRNA and their targets | url = http://crdd.osdd.net/servers/virmirna| publisher = Bioinformatics center, CSIR-IMTECH }} The expression of transcription activators by ''[[human herpesvirus-6]]'' DNA is believed to be regulated by viral miRNA.{{cite journal | vauthors = Tuddenham L, Jung JS, Chane-Woon-Ming B, Dölken L, Pfeffer S | title = Small RNA deep sequencing identifies microRNAs and other small noncoding RNAs from human herpesvirus 6B | journal = Journal of Virology | volume = 86 | issue = 3 | pages = 1638–49 | date = February 2012 | pmid = 22114334 | pmc = 3264354 | doi = 10.1128/JVI.05911-11 }} [247] => [248] => ==Target prediction== [249] => {{See also|List of RNA structure prediction software#Inter molecular interactions: MicroRNA:UTR}}miRNAs can bind to target messenger RNA (mRNA) transcripts of protein-coding genes and negatively control their translation or cause mRNA degradation. It is of key importance to identify the miRNA targets accurately.{{cite journal | vauthors = Zheng H, Fu R, Wang JT, Liu Q, Chen H, Jiang SW | title = Advances in the techniques for the prediction of microRNA targets | journal = International Journal of Molecular Sciences | volume = 14 | issue = 4 | pages = 8179–87 | date = April 2013 | pmid = 23591837 | pmc = 3645737 | doi = 10.3390/ijms14048179 | doi-access = free }} A comparison of the predictive performance of eighteen ''in silico'' algorithms is available.{{cite journal | vauthors = Agarwal V, Bell GW, Nam JW, Bartel DP | title = Predicting effective microRNA target sites in mammalian mRNAs | journal = eLife | volume = 4 | pages = e05005 | date = August 2015 | pmid = 26267216 | pmc = 4532895 | doi = 10.7554/eLife.05005 | doi-access = free }} Large scale studies of functional miRNA targeting suggest that many functional miRNAs can be missed by target prediction algorithms. [250] => [251] => == See also == [252] => {{Portal|Biology}} [253] => * [[Anti-miRNA oligonucleotides]] [254] => * [[Gene expression]] [255] => * [[List of RNA structure prediction software#Family specific gene prediction software|List of miRNA gene prediction tools]] [256] => * [[List of RNA structure prediction software#Intermolecular interactions: MicroRNA:UTR|List of miRNA target prediction tools]] [257] => * [[MicroDNA]] [258] => *[[MicroRNA Biosensors]] [259] => * [[MiRNEST]] [260] => * [[MIR222]] [261] => * [[miR-324-5p]] [262] => * [[RNA interference]] [263] => * [[Small interfering RNA]] [264] => * [[Small nucleolar RNA-derived microRNA]] [265] => * [[C19MC miRNA cluster]] [266] => [267] => == References == [268] => {{Reflist|30em}} [269] => [270] => == Further reading == [271] => {{refbegin}} [272] => * miRNA definition and classification: {{cite journal | vauthors = Ambros V, Bartel B, Bartel DP, Burge CB, Carrington JC, Chen X, Dreyfuss G, Eddy SR, Griffiths-Jones S, Marshall M, Matzke M, Ruvkun G, Tuschl T | title = A uniform system for microRNA annotation | journal = RNA | volume = 9 | issue = 3 | pages = 277–9 | date = March 2003 | pmid = 12592000 | pmc = 1370393 | doi = 10.1261/rna.2183803 }} [273] => * ''[[Science (journal)|Science]]'' review of small RNA: {{cite journal | vauthors = Baulcombe D | title = DNA events. An RNA microcosm | journal = Science | volume = 297 | issue = 5589 | pages = 2002–3 | date = September 2002 | pmid = 12242426 | doi = 10.1126/science.1077906 | s2cid = 82531727 }} [274] => * Discovery of ''lin-4'', the first miRNA to be discovered: {{cite journal | vauthors = Lee RC, Feinbaum RL, Ambros V | title = The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 | journal = Cell | volume = 75 | issue = 5 | pages = 843–54 | date = December 1993 | pmid = 8252621 | doi = 10.1016/0092-8674(93)90529-Y | doi-access = free }} [275] => {{refend}} [276] => [277] => == External links == [278] => {{Wiktionary|microRNA|miRNA}} [279] => {{Prone to spam|date=February 2016}} [280] => [295] => * [http://www.mirbase.org/ The miRBase database] [296] => * [http://mirtarbase.mbc.nctu.edu.tw/ miRTarBase], the experimentally validated microRNA-target interactions database. [297] => * [http://www.bioinfocabd.upo.es/semirna/ semirna], Web application to search for microRNAs in a plant genome. [298] => * [http://onco.io/ ONCO.IO]: Integrative resource for microRNA and transcription factors analysis in cancer. [299] => * [http://mirob.interactome.ru/ MirOB] {{Webarchive|url=https://web.archive.org/web/20140304103852/http://mirob.interactome.ru/ |date=4 March 2014 }}: MicroRNA targets database and data analysis and dataviz tool. [300] => * [http://rna.sysu.edu.cn/chipbase/ ChIPBase database]: An open access database for decoding the [[transcription factors]] that were involved in or affected the transcription of microRNAs from ChIP-seq data. [301] => * [https://www.youtube.com/watch?v=_-9pROnSD-A An animated video of the microRNA biogenesis process]. [302] => * [http://dharmacon.horizondiscovery.com/rnai/microrna/ miRNA modulation reagents] to enable up-regulation or suppression of endogenous mature microRNA function [303] => [305] => [306] => {{miRNA precursor families}} [307] => {{Natural antisense transcripts}} [308] => {{Nucleic acids}} [309] => [310] => [[Category:MicroRNA| ]] [311] => [[Category:Gene expression]] [312] => [[Category:RNA]] [313] => [[Category:Non-coding RNA]] [] => )
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MicroRNA

MicroRNA (miRNA) is a small, non-coding RNA molecule that plays a crucial role in regulating gene expression. It was first discovered in the early 1990s and has since been found in a wide range of organisms, including humans.

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It was first discovered in the early 1990s and has since been found in a wide range of organisms, including humans. MiRNAs are transcribed from DNA, but unlike protein-coding genes, they do not produce proteins. Instead, they function by binding to messenger RNA (mRNA) molecules and either suppressing their translation or promoting their degradation. This regulatory mechanism allows miRNAs to fine-tune gene expression and control various biological processes, including development, cell differentiation, and metabolism. The discovery of miRNAs has revolutionized our understanding of gene regulation and has opened up new avenues for research in multiple fields, including cancer, neurobiology, and infectious diseases. In cancer, aberrant expression of certain miRNAs has been linked to tumor initiation, progression, and metastasis. Furthermore, miRNAs have shown promise as potential therapeutic targets, with ongoing efforts to develop miRNA-based drugs for various diseases. The Wikipedia page on microRNA provides detailed information on the discovery, biogenesis, and functions of miRNAs, as well as their involvement in diseases and potential clinical applications. It also includes a list of notable miRNAs and references to further reading on the topic.

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