Editing MicroRNA (section)

==Human and animal diseases==
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.<ref>{{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 }}</ref>

===Inherited diseases===
A mutation in the seed region of miR-96 causes hereditary progressive hearing loss.<ref name="pmid19363479">{{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 }}</ref>

A mutation in the seed region of miR-184 causes hereditary keratoconus with anterior polar cataract.<ref>{{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 }}</ref>

Deletion of the miR-17~92 cluster causes skeletal and growth defects.<ref name="pmid21892160">{{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 }}</ref>

===Cancer===
[[File:Role of miRNA in a cancer cell.svg|right|thumb|Role of miRNA in a cancer cell]]

The first human disease known to be associated with miRNA deregulation was [[chronic lymphocytic leukemia]].<ref name="pmid15284443">{{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 }}</ref> Many other miRNAs also have links with cancer and accordingly are sometimes referred to as "[[oncomir]]s".<ref>{{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 | hdl = 11577/3478062 | hdl-access = free }}</ref> 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.<ref name="pmid36010971">{{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 }}</ref>

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]]<nowiki/>a levels may serve as an indicator of poor survival.<ref name="pmid21748820">{{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 }}</ref> Either high miR-185 or low miR-133b levels may correlate with [[metastasis]] and poor survival in [[colorectal cancer]].<ref name="pmid21573504">{{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 = 311–18 | date = August 2011 | pmid = 21573504 | doi = 10.3892/ijo.2011.1043 | doi-access = free }}</ref>

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.<ref name="pmid27271572">{{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 }}</ref> In-vitro studies suggested that miR-205 and miR-373 may functionally induce different features of mucinous-associated neoplastic progression in intestinal epithelial cells.<ref name="pmid27271572"/>

Hepatocellular carcinoma cell proliferation may arise from miR-21 interaction with MAP2K3, a tumor repressor gene.<ref name="pmid24112539">MicroRNA-21 promotes hepatocellular carcinoma HepG2 cell proliferation through repression of mitogen-activated protein kinase-kinase 3. Guangxian Xu et al., 2013</ref> 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.<ref>{{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 }}</ref> 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.

MicroRNAs have the potential to be used as tools or targets for treatment of different cancers.<ref name= Hosseinahli2018>{{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 }}</ref> 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.<ref name="Liu_2014">{{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 }}</ref><ref name="Wen_2015">{{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 }}</ref>

===DNA repair and cancer===
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.<ref>{{cite journal|url=
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}}</ref>
Cancer is caused by the accumulation of [[mutation]]s from either DNA damage or uncorrected errors in [[DNA replication]].<ref>{{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 }}</ref> Defects in [[DNA repair]] cause the accumulation of mutations, which can lead to cancer.<ref>{{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}}</ref> Several genes involved in DNA repair are regulated by microRNAs.<ref>{{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 }}</ref>

[[Germline]] mutations in DNA repair genes cause only 2–5% of [[colon cancer]] cases.<ref>{{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 }}</ref> 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.<ref>{{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 }}</ref> 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.<ref>{{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 = 6982–87 | date = April 2010 | pmid = 20351277 | pmc = 2872463 | doi = 10.1073/pnas.1002472107 | bibcode = 2010PNAS..107.6982V | doi-access = free }}</ref>

In 29–66%<ref name=Zhang>{{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 = 712–19 | date = June 2012 | pmid = 22570426 | pmc = 3367855 | doi = 10.1093/neuonc/nos089 }}</ref><ref>{{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 }}</ref> 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.<ref name=Zhang /> 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).<ref name=Zhang /> Thus, in 28% of glioblastomas, increased expression of miR-181d and reduced expression of DNA repair enzyme MGMT may be a causal factor.

[[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.<ref>{{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 | bibcode = 2004FEBSL.574....1S | s2cid = 28903539 }}</ref> 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.<ref>{{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 = 3371–75 | date = May 2004 | pmid = 15150086 | doi = 10.1158/0008-5472.CAN-04-0044 | doi-access = free }}</ref> HMGA2 protein specifically targets the promoter of [[ERCC1]], thus reducing expression of this DNA repair gene.<ref>{{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 }}</ref> ERCC1 protein expression was deficient in 100% of 47 evaluated colon cancers (though the extent to which HGMA2 was involved is not known).<ref>{{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 }}</ref>

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

===Heart disease===
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.<ref name="pmid18256189">{{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 = 2111–16 | date = February 2008 | pmid = 18256189 | pmc = 2542870 | doi = 10.1073/pnas.0710228105 | bibcode = 2008PNAS..105.2111C |doi-access=free}}</ref><ref name="2007-Zhao">{{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 }}</ref> miRNA expression profiling studies demonstrate that expression levels of specific miRNAs change in diseased human hearts, pointing to their involvement in [[Cardiomyopathy|cardiomyopathies]].<ref name="pmid17606841">{{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 }}</ref><ref name="pmid17108080">{{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 }}</ref><ref name="pmid17498736">{{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 }}</ref> 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.<ref name="2007-Zhao"/><ref>{{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 }}</ref><ref name="pmid17401374">{{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 }}</ref><ref name="pmid17468766">{{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 = 613–18 | date = May 2007 | pmid = 17468766 | doi = 10.1038/nm1582 | s2cid = 10097893 }}</ref><ref name="pmid17379774">{{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 = 575–79 | date = April 2007 | pmid = 17379774 | doi = 10.1126/science.1139089 | bibcode = 2007Sci...316..575V | s2cid = 1927839 }}</ref> Another role for miRNA in cardiovascular diseases is to use their expression levels for diagnosis, prognosis or risk stratification.<ref>{{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 }}</ref> miRNA's in animal models have also been linked to cholesterol metabolism and regulation.

====miRNA-712====
[[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.<ref>{{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 }}</ref> 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).<ref name="Son_2013">{{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 }}</ref> A number of pro-atherogenic genes including [[matrix metalloproteinase]]s (MMPs) are upregulated by d-flow,<ref name="Son_2013" /> 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.<ref name="Son_2013" /> Coinciding with these results, miR-712 is also upregulated in endothelial cells exposed to&nbsp;naturally occurring d-flow&nbsp;in the greater curvature of the aortic arch.<ref name="Son_2013" />

====Origin====
Pre-mRNA sequence of miR-712 is generated from the murine ribosomal RN45s gene at the [[internal transcribed spacer]] region 2 (ITS2).<ref name="Son_2013" /> XRN1 is an exonuclease that degrades the ITS2 region during processing of RN45s.<ref name="Son_2013" /> Reduction of XRN1 under d-flow'' ''conditions therefore leads to the accumulation of miR-712.<ref name="Son_2013" />

====Mechanism====
MiR-712 targets tissue inhibitor of [[Metalloproteinase|metalloproteinases 3]] (TIMP3).<ref name="Son_2013" /> 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.<ref name=":1">{{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 }}</ref> These fibers play a critical role in regulation of vascular inflammation and permeability, which are important in the development of atherosclerosis.<ref>{{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 }}</ref> Expressed by endothelial cells, TIMP3 is the only ECM-bound TIMP.<ref name=":1" /> 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.<ref name="Son_2013" />

TIMP3 also decreases the expression of TNFα (a pro-inflammatory regulator) during turbulent flow.<ref name="Son_2013" /> 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,<ref name="Son_2013" /> suggesting that miR-712 and TIMP3 regulate TACE activity in turbulent flow conditions.

Anti-miR-712 effectively suppresses d-flow-induced miR-712 expression and increases TIMP3 expression.<ref name="Son_2013" /> Anti-miR-712 also inhibits vascular hyperpermeability, thereby significantly reducing atherosclerosis lesion development and immune cell infiltration.<ref name="Son_2013" />

====Human homolog microRNA-205====

The human homolog of miR-712 was found on the RN45s homolog gene, which maintains similar miRNAs to mice.<ref name="Son_2013" /> MiR-205 of humans share similar sequences with miR-712 of mice and is conserved across most vertebrates.<ref name="Son_2013" /> MiR-205 and miR-712 also share more than 50% of the cell signaling targets, including TIMP3.<ref name="Son_2013" />

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.<ref name="Son_2013" />

===Kidney disease===
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.<ref name="ReferenceB">{{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 }}</ref> 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.<ref name="ReferenceB"/>

===Nervous system===
MiRNAs are crucial for the healthy development and function of the [[nervous system]].<ref>{{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 }}</ref> Previous studies demonstrate that miRNAs can regulate neuronal differentiation and maturation at various stages.<ref>{{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 }}</ref> MiRNAs also play important roles in [[Synaptogenesis|synaptic development]]<ref name="pmid19888283">{{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 }}</ref> (such as dendritogenesis or spine morphogenesis) and [[synaptic plasticity]]<ref>{{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 }}</ref> (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<ref>{{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 }}</ref>), and neurodegeneration (when silenced in [[forebrain]] neurons<ref>{{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 }}</ref>). Altered miRNA expression has been found in neurodegenerative diseases (such as [[Alzheimer's disease]], [[Parkinson's disease]], and [[Huntington's disease]]<ref>{{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 }}</ref>) as well as many psychiatric disorders (including [[epilepsy]],<ref>{{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 }}</ref> [[schizophrenia]], [[major depressive disorder|major depression]], [[bipolar disorder]], and [[anxiety disorder]]s<ref name="Hommers LG, Domschke K, Deckert J 2015 79-97">{{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 }}</ref><ref name="pmid19568434">{{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 }}</ref><ref name="pmid19721432">{{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 }}</ref>).

====Stroke====
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]]s, 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.<ref>{{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}}</ref><ref name=":0">{{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 }}</ref> 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.<ref>{{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 }}</ref>&nbsp;

====Alcoholism====
The vital role of miRNAs in gene expression is significant to [[addiction]], specifically [[alcoholism]].<ref name="Lewohl">{{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 }}</ref> Chronic alcohol abuse results in persistent changes in brain function mediated in part by alterations in [[gene expression]].<ref name="Lewohl" /> 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 [[Alcohol dependence|dependence]].<ref name="Tapocik1">{{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 }}</ref> 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]].<ref name="Lewohl" /> 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.<ref name="Gorini">{{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 }}</ref>

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.<ref name="Tapocik2">{{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 = 4581–88 | date = March 2014 | pmid = 24672003 | pmc = 3965783 | doi = 10.1523/JNEUROSCI.0445-14.2014 }}</ref> [[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.<ref name="Lippai">{{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 }}</ref> 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.<ref name="Li">{{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 }}</ref> 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.<ref name="Li" />

===Obesity===
miRNAs play crucial roles in the regulation of [[stem cell]] progenitors differentiating into [[adipocyte]]s.<ref name="pmid21844119">{{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 }}</ref> 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.<ref name="pmid21756067">{{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 }}</ref> 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]]).<ref name="pmid16431920">{{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 = 7960–67 | date = March 2006 | pmid = 16431920 | doi = 10.1074/jbc.M510682200 | doi-access = free }}</ref> This paves the way for possible genetic obesity treatments.

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]].<ref name="Jun-HaoGupta2016">{{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 }}</ref> 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]].<ref name="pmid21962509">{{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  }}</ref> 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.<ref name="pmid22160727">{{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 }}</ref> These experimental findings suggest that let-7 inhibition could represent a new therapy for [[obesity]] and type 2 diabetes.

===Hemostasis===
miRNAs also play crucial roles in the regulation of complex enzymatic cascades including the [[Hemostasis|hemostatic blood coagulation system]].<ref name="pmid25400249">{{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 }}</ref> Large scale studies of functional miRNA targeting have recently uncovered rationale therapeutic targets in the hemostatic system.<ref name="pmid30207063">{{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 }}</ref><ref name="pmid32898547">{{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 }}</ref> They have been directly linked to [[Calcium metabolism|Calcium homeostasis]] in the [[endoplasmic reticulum]], which is critical in cell differentiation in early development.<ref>{{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 }}</ref>