Editing MicroRNA (section)

==History==
The first miRNA was discovered in the early 1990s.<ref name="pmid8252621">{{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 }}</ref> However, they were not recognized as a distinct class of biological regulators until the early 2000s.<ref name="pmid10706289">{{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 = 901–06 | date = February 2000 | pmid = 10706289 | doi = 10.1038/35002607 | bibcode = 2000Natur.403..901R | s2cid = 4384503 }}</ref><ref name="pmid11081512">{{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 = 86–89 | date = November 2000 | pmid = 11081512 | doi = 10.1038/35040556 | bibcode = 2000Natur.408...86P | s2cid = 4401732 }}</ref><ref name="pmid11679670">{{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 = 853–58 | 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 }}</ref><ref name="pmid11679671">{{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 }}</ref><ref name="pmid11679672">{{cite journal | vauthors = Lee RC, Ambros V | title = An extensive class of small RNAs in Caenorhabditis elegans | journal = Science | volume = 294 | issue = 5543 | pages = 862–64 | date = October 2001 | pmid = 11679672 | doi = 10.1126/science.1065329 | bibcode = 2001Sci...294..862L | s2cid = 33480585 }}</ref> Research revealed different sets of miRNAs expressed in different cell types and [[Tissue (biology)|tissues]]<ref name="pmid12007417" /><ref>{{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 = 310–11 | date = July 2005 | pmid = 15919954 | doi = 10.1126/science.1114519 | bibcode = 2005Sci...309..310W | s2cid = 38939571 }}</ref> and multiple roles for miRNAs in plant and animal development and in many other biological processes.<ref name="ReferenceA" /><ref name="pmid12679032">{{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 }}</ref><ref name="pmid16423811">{{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 }}</ref><ref name="pmid15538371">{{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 }}</ref><ref name="pmid14657504">{{cite journal | vauthors = Chen CZ, Li L, Lodish HF, Bartel DP | title = MicroRNAs modulate hematopoietic lineage differentiation | journal = Science | volume = 303 | issue = 5654 | pages = 83–86 | date = January 2004 | pmid = 14657504 | doi = 10.1126/science.1091903 | bibcode = 2004Sci...303...83C | hdl = 1721.1/7483 | s2cid = 7044929 | hdl-access = free }}</ref><ref name="pmid17521938">{{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 }}</ref><ref name="pmid16040801">{{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 }}</ref> Aberrant miRNA expression are implicated in disease states. MiRNA-based therapies are under investigation.<ref name="pmid19956180">{{cite journal | vauthors = Trang P, Weidhaas JB, Slack FJ | title = MicroRNAs as potential cancer therapeutics | journal = Oncogene | volume = 27 | issue = Suppl 2 | pages = S52–57 | date = December 2008 | pmid = 19956180 | doi = 10.1038/onc.2009.353 | pmc = 10033140 | doi-access = free }}</ref><ref name="pmid19876744">{{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 }}</ref><ref name="pmid19896977">{{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 }}</ref><ref>{{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 }}</ref>

The first miRNA was discovered in 1993 by a group led by [[Victor Ambros]] and including Lee and Feinbaum. However, additional insight into its mode of action required simultaneously published work by [[Gary Ruvkun]]'s team, including Wightman and Ha.<ref name="pmid8252621" /><ref name="pmid8252622">{{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 }}</ref> 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.&nbsp;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.<ref name="pmid8252621" /> 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.

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.&nbsp;elegans''.<ref name="pmid10706289" /> 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.<ref name="pmid11081512" />

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.&nbsp;elegans'', ''[[Drosophila]]'' and human cells.<ref name="pmid11679670" /><ref name="pmid11679671" /><ref name="pmid11679672" /> 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.<ref name="pmid11679670" /><ref name="pmid11679671" /><ref name="pmid11679672" />

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.]]<ref>{{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 }}</ref>