Editing Gene expression (section)

===Three prime untranslated regions and microRNAs===
{{main|Three prime untranslated region}}
{{main|MicroRNA}}
[[Three prime untranslated region]]s (3′UTRs) of [[messenger RNA]]s (mRNAs) often contain regulatory sequences that post-transcriptionally influence gene expression. Such 3′-UTRs often contain both binding sites for [[microRNA]]s (miRNAs) as well as for regulatory proteins.<ref>{{cite journal | vauthors = Mayr C | title = What Are 3' UTRs Doing? | journal = Cold Spring Harbor Perspectives in Biology | volume = 11 | issue = 10 | pages = a034728 | date = October 2019 | pmid = 30181377 | pmc = 6771366 | doi = 10.1101/cshperspect.a034728 }}</ref> By binding to specific sites within the 3′-UTR, miRNAs can decrease gene expression of various mRNAs by either inhibiting translation or directly causing degradation of the transcript.<ref>{{cite journal | vauthors = O'Brien J, Hayder H, Zayed Y, Peng C | title = Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation | journal = Frontiers in Endocrinology | volume = 9 | pages = 402 | date = 2018-08-03 | pmid = 30123182 | pmc = 6085463 | doi = 10.3389/fendo.2018.00402 | doi-access = free }}</ref> The 3′-UTR also may have silencer regions that bind repressor proteins that inhibit the expression of a mRNA.<ref>{{cite journal | vauthors = Mayya VK, Duchaine TF | title = Ciphers and Executioners: How 3'-Untranslated Regions Determine the Fate of Messenger RNAs | journal = Frontiers in Genetics | volume = 10 | pages = 6 | date = 2019-01-24 | pmid = 30740123 | pmc = 6357968 | doi = 10.3389/fgene.2019.00006 | doi-access = free }}</ref>

The 3′-UTR often contains [[Three prime untranslated region#MicroRNA response elements|microRNA response elements (MREs)]]. MREs are sequences to which miRNAs bind. These are prevalent motifs within 3′-UTRs. Among all regulatory motifs within the 3′-UTRs (e.g. including silencer regions), MREs make up about half of the motifs.<ref>{{cite journal | vauthors = Nair AA, Tang X, Thompson KJ, Vedell PT, Kalari KR, Subramanian S | title = Frequency of MicroRNA Response Elements Identifies Pathologically Relevant Signaling Pathways in Triple-Negative Breast Cancer | journal = iScience | volume = 23 | issue = 6 | pages = 101249 | date = June 2020 | pmid = 32629614 | pmc = 7322352 | doi = 10.1016/j.isci.2020.101249 | bibcode = 2020iSci...23j1249N }}</ref>

As of 2014, the [[miRBase]] web site,<ref>miRBase.org</ref> an archive of [[microRNA|miRNA]] [[Sequence (biology)|sequences]] and annotations, listed 28,645 entries in 233 biologic species. Of these, 1,881 miRNAs were in annotated human miRNA loci. miRNAs were predicted to have an average of about four hundred target [[messenger RNA|mRNAs]] (affecting expression of several hundred genes).<ref name=Friedman>{{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 }}</ref> Friedman et al.<ref name=Friedman /> estimate that >45,000 miRNA target sites within human mRNA 3′UTRs are conserved above background levels, and >60% of human protein-coding genes have been under selective pressure to maintain pairing to miRNAs.

Direct experiments show that a single miRNA can reduce the stability of hundreds of unique mRNAs.<ref name="pmid15685193">{{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 = 769–773 | date = February 2005 | pmid = 15685193 | doi = 10.1038/nature03315 | s2cid = 4430576 | bibcode = 2005Natur.433..769L }}</ref> Other experiments show that a single miRNA may repress the production of hundreds of proteins, but that this repression often is relatively mild (less than 2-fold).<ref>{{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 | s2cid = 4429008 | bibcode = 2008Natur.455...58S }}</ref><ref>{{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 | bibcode = 2008Natur.455...64B }}</ref>

The effects of miRNA dysregulation of gene expression seem to be important in cancer.<ref name="pmid21931505">{{cite journal | vauthors = Palmero EI, de Campos SG, Campos M, de Souza NC, Guerreiro ID, Carvalho AL, Marques MM | title = Mechanisms and role of microRNA deregulation in cancer onset and progression | journal = Genetics and Molecular Biology | volume = 34 | issue = 3 | pages = 363–370 | date = July 2011 | pmid = 21931505 | pmc = 3168173 | doi = 10.1590/S1415-47572011000300001 }}</ref> For instance, in gastrointestinal cancers, nine miRNAs have been identified as [[Epigenetics|epigenetically]] altered and effective in down regulating DNA repair enzymes.<ref name="pmid25987950">{{cite journal | vauthors = Bernstein C, Bernstein H | title = Epigenetic reduction of DNA repair in progression to gastrointestinal cancer | journal = World Journal of Gastrointestinal Oncology | volume = 7 | issue = 5 | pages = 30–46 | date = May 2015 | pmid = 25987950 | pmc = 4434036 | doi = 10.4251/wjgo.v7.i5.30 | doi-access = free }}</ref>

The effects of miRNA dysregulation of gene expression also seem to be important in neuropsychiatric disorders, such as schizophrenia, bipolar disorder, major depression, Parkinson's disease, Alzheimer's disease and autism spectrum disorders.<ref name="pmid22539927">{{cite journal | vauthors = Mellios N, Sur M | title = The Emerging Role of microRNAs in Schizophrenia and Autism Spectrum Disorders | journal = Frontiers in Psychiatry | volume = 3 | pages = 39 | year = 2012 | pmid = 22539927 | pmc = 3336189 | doi = 10.3389/fpsyt.2012.00039 | doi-access = free }}</ref><ref name="pmid25636176">{{cite journal | vauthors = Geaghan M, Cairns MJ | title = MicroRNA and Posttranscriptional Dysregulation in Psychiatry | journal = Biological Psychiatry | volume = 78 | issue = 4 | pages = 231–239 | date = August 2015 | pmid = 25636176 | doi = 10.1016/j.biopsych.2014.12.009 | hdl-access = free | doi-access = free | hdl = 1959.13/1335073 }}</ref>