Editing MicroRNA (section)

==Cellular functions==
[[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.<ref name="Zinovyev_2012" /> 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.]]

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.<ref>{{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 }}</ref> Perfect or near perfect base pairing with the target RNA promotes cleavage of the RNA.<ref>{{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 = 211–12 | year = 2004 | pmid = 17150553 | doi = 10.1093/nass/48.1.211 | doi-access = free }}</ref> This is the primary mode of plant miRNAs.<ref name=Moxon2008>{{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 = 1602–09 | date = October 2008 | pmid = 18653800 | pmc = 2556272 | doi = 10.1101/gr.080127.108 }}</ref> In animals the match-ups are imperfect.

For partially complementary microRNAs to recognise their targets, nucleotides 2–7 of the miRNA (its 'seed region'<ref name="Lewis BP, Burge CB, Bartel DP 2005 15–20" /><ref name="Lewis BP, Shih IH, Jones-Rhoades M, Bartel DP, Burge CB 2003 787–798" />) must be perfectly complementary.<ref>{{cite journal | vauthors = Mazière P, Enright AJ | title = Prediction of microRNA targets | journal = Drug Discovery Today | volume = 12 | issue = 11–12 | pages = 452–58 | date = June 2007 | pmid = 17532529 | doi = 10.1016/j.drudis.2007.04.002 }}</ref> Animal miRNAs inhibit protein translation of the target mRNA<ref>{{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 | pmc = 11131689 }}</ref> (this is present but less common in plants).<ref name="Moxon2008" /> Partially complementary microRNAs can also speed up [[deadenylation]], causing mRNAs to be degraded sooner.<ref>{{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 }}</ref> 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.<ref name="pmid22422859">{{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 = 233–37 | date = April 2012 | pmid = 22422859 | pmc = 3547538 | doi = 10.1126/science.1215704 | bibcode = 2012Sci...336..233B }}</ref><ref name="pmid22499947">{{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 }}</ref>

miRNAs occasionally also cause [[Histone#Chromatin regulation|histone modification]] and [[DNA methylation]] of [[Promoter (biology)|promoter]] sites, which affects the expression of target genes.<ref name="pmid19232136">{{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 }}</ref><ref name="pmid18256543">{{cite journal | vauthors = Hawkins PG, Morris KV | title = RNA and transcriptional modulation of gene expression | journal = Cell Cycle | volume = 7 | issue = 5 | pages = 602–07 | date = March 2008 | pmid = 18256543 | pmc = 2877389 | doi = 10.4161/cc.7.5.5522 }}</ref>

Nine mechanisms of miRNA action are described and assembled in a unified mathematical model:<ref name="Zinovyev_2012">{{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}}</ref>
* Cap-40S initiation inhibition;
* 60S Ribosomal unit joining inhibition;
* Elongation inhibition;
* Ribosome drop-off (premature termination);
* Co-translational nascent protein degradation;
* Sequestration in [[P-bodies]];
* mRNA decay (destabilisation);
* mRNA cleavage;
* Transcriptional inhibition through microRNA-mediated chromatin reorganization followed by gene silencing.
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''.<ref name="Zinovyev_2012" />

Unlike plant microRNAs, the animal microRNAs target diverse genes.<ref name="Lewis BP, Shih IH, Jones-Rhoades M, Bartel DP, Burge CB 2003 787–798" /> 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.<ref>{{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 }}</ref> There is a strong correlation between ''ITPR'' gene regulations and mir-92 and mir-19.<ref>{{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 }}</ref>

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 RNA]]s (saRNAs),<ref name= LiLC>{{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}}</ref> but has also been demonstrated for endogenous microRNA.<ref>{{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 }}{{Erratum|doi=10.1073/pnas.1803343115|pmid=29555737|http://retractionwatch.com/2018/03/20/ucsf-va-investigation-finds-misconduct-in-highly-cited-pnas-paper/ ''Retraction Watch''|https://retractionwatch.com/2022/12/08/professor-emeritus-loses-fourth-paper-after-ucsf-va-investigation-five-years-after-other-retractions/ ''Retraction Watch''|checked=yes}}</ref>

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]].<ref name="pmid21802130">{{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 = 353–58 | date = August 2011 | pmid = 21802130 | pmc = 3235919 | doi = 10.1016/j.cell.2011.07.014 }}</ref>

miRNAs are also found as [[Extracellular RNA|extracellular]] '''circulating miRNAs'''.<ref name=Kumar>{{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=}}</ref> 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.<ref name=Kumar/><ref name=PN>{{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 }}</ref> 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.<ref>{{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 }}</ref>

Moreover, miRNA as [[miR-183/96/182]] seems to play a key role in [[circadian rhythm]].<ref>{{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 }}
*{{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}}</ref>