Editing Gene expression (section)

====Enhancers, transcription factors, mediator complex and DNA loops in mammalian transcription====
[[File:Regulation of transcription in mammals.jpg|thumb|left|500px| '''Regulation of transcription in mammals'''. An active [[Enhancer (genetics)|enhancer]] regulatory region is enabled to interact with the [[Promoter (genetics)|promoter]] region of its target [[gene]] by formation of a chromosome loop. This can initiate [[messenger RNA]] (mRNA) synthesis by [[RNA polymerase II]] (RNAP II) bound to the promoter at the [[Transcription (biology)|transcription start site]] of the gene. The loop is stabilized by one architectural protein anchored to the enhancer and one anchored to the promoter and these proteins are joined to form a dimer (red zigzags). Specific regulatory [[transcription factor]]s bind to DNA sequence motifs on the enhancer. General transcription factors bind to the promoter. When a transcription factor is activated by a signal (here indicated as [[phosphorylation]] shown by a small red star on a transcription factor on the enhancer) the enhancer is activated and can now activate its target promoter. The active enhancer is transcribed on each strand of DNA in opposite directions by bound RNAP IIs. Mediator proteins (a complex consisting of about 26 proteins in an interacting structure) communicate regulatory signals from the enhancer DNA-bound transcription factors to the promoter.]]

Gene expression in mammals is regulated by many [[cis-regulatory element]]s, including [[Promoter (genetics)|core promoters and promoter-proximal elements]] that are located near the [[Eukaryotic transcription|transcription start sites]] of genes, [[Upstream and downstream (DNA)|upstream]] on the DNA (towards the 5' region of the [[sense strand]]). Other important cis-regulatory modules are localized in DNA regions that are distant from the transcription start sites. These include [[Enhancer (genetics)|enhancers]], [[Silencer (genetics)|silencers]], [[Insulator (genetics)|insulators]] and tethering elements.<ref name="pmid33102493">{{cite journal | vauthors = Verheul TC, van Hijfte L, Perenthaler E, Barakat TS | title = The Why of YY1: Mechanisms of Transcriptional Regulation by Yin Yang 1 | journal = Frontiers in Cell and Developmental Biology | volume = 8 | issue =  | pages = 592164 | date = 2020 | pmid = 33102493 | pmc = 7554316 | doi = 10.3389/fcell.2020.592164 | doi-access = free }}</ref> Enhancers and their associated [[transcription factors]] have a leading role in the regulation of gene expression.<ref name="pmid22868264">{{cite journal | vauthors = Spitz F, Furlong EE | title = Transcription factors: from enhancer binding to developmental control | journal = Nature Reviews. Genetics | volume = 13 | issue = 9 | pages = 613–626 | date = September 2012 | pmid = 22868264 | doi = 10.1038/nrg3207 | s2cid = 205485256 }}</ref>

[[Enhancer (genetics)|Enhancers]] are genome regions that regulate genes. Enhancers control cell-type-specific gene expression programs, most often by looping through long distances to come in physical proximity with the promoters of their target genes.<ref name=Schoenfelder>{{cite journal | vauthors = Schoenfelder S, Fraser P | title = Long-range enhancer-promoter contacts in gene expression control | journal = Nature Reviews. Genetics | volume = 20 | issue = 8 | pages = 437–455 | date = August 2019 | pmid = 31086298 | doi = 10.1038/s41576-019-0128-0 | s2cid = 152283312 }}</ref> Multiple enhancers, each often tens or hundred of thousands of nucleotides distant from their target genes, loop to their target gene promoters and coordinate with each other to control gene expression.<ref name=Schoenfelder />

The illustration shows an enhancer looping around to come into proximity with the promoter of a target gene. The loop is stabilized by a dimer of a connector protein (e.g. dimer of [[CTCF]] or [[YY1]]). One member of the dimer is anchored to its binding motif on the enhancer and the other member is anchored to its binding motif on the promoter (represented by the red zigzags in the illustration).<ref name="pmid29224777">{{cite journal | vauthors = Weintraub AS, Li CH, Zamudio AV, Sigova AA, Hannett NM, Day DS, Abraham BJ, Cohen MA, Nabet B, Buckley DL, Guo YE, Hnisz D, Jaenisch R, Bradner JE, Gray NS, Young RA | title = YY1 Is a Structural Regulator of Enhancer-Promoter Loops | journal = Cell | volume = 171 | issue = 7 | pages = 1573–1588.e28 | date = December 2017 | pmid = 29224777 | pmc = 5785279 | doi = 10.1016/j.cell.2017.11.008 }}</ref> Several cell function-specific transcription factors (among the about 1,600 transcription factors in a human cell)<ref name="pmid29425488">{{cite journal | vauthors = Lambert SA, Jolma A, Campitelli LF, Das PK, Yin Y, Albu M, Chen X, Taipale J, Hughes TR, Weirauch MT | title = The Human Transcription Factors | journal = Cell | volume = 172 | issue = 4 | pages = 650–665 | date = February 2018 | pmid = 29425488 | doi = 10.1016/j.cell.2018.01.029 | doi-access = free }}</ref> generally bind to specific motifs on an enhancer.<ref name="pmid29987030">{{cite journal | vauthors = Grossman SR, Engreitz J, Ray JP, Nguyen TH, Hacohen N, Lander ES | title = Positional specificity of different transcription factor classes within enhancers | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 115 | issue = 30 | pages = E7222–E7230 | date = July 2018 | pmid = 29987030 | pmc = 6065035 | doi = 10.1073/pnas.1804663115 | doi-access = free | bibcode = 2018PNAS..115E7222G }}</ref> A small combination of these enhancer-bound transcription factors, when brought close to a promoter by a DNA loop, govern transcription level of the target gene. Mediator (a complex usually consisting of about 26 proteins in an interacting structure) communicates regulatory signals from enhancer DNA-bound transcription factors directly to the RNA polymerase II (pol II) enzyme bound to the promoter.<ref name="pmid25693131">{{cite journal | vauthors = Allen BL, Taatjes DJ | title = The Mediator complex: a central integrator of transcription | journal = Nature Reviews. Molecular Cell Biology | volume = 16 | issue = 3 | pages = 155–166 | date = March 2015 | pmid = 25693131 | pmc = 4963239 | doi = 10.1038/nrm3951 }}</ref>

Enhancers, when active, are generally transcribed from both strands of DNA with RNA polymerases acting in two different directions, producing two eRNAs as illustrated in the figure.<ref name="pmid29378788">{{cite journal | vauthors = Mikhaylichenko O, Bondarenko V, Harnett D, Schor IE, Males M, Viales RR, Furlong EE | title = The degree of enhancer or promoter activity is reflected by the levels and directionality of eRNA transcription | journal = Genes & Development | volume = 32 | issue = 1 | pages = 42–57 | date = January 2018 | pmid = 29378788 | pmc = 5828394 | doi = 10.1101/gad.308619.117 }}</ref> An inactive enhancer may be bound by an inactive transcription factor. Phosphorylation of the transcription factor may activate it and that activated transcription factor may then activate the enhancer to which it is bound (see small red star representing phosphorylation of transcription factor bound to enhancer in the illustration).<ref name="pmid12514134">{{cite journal | vauthors = Li QJ, Yang SH, Maeda Y, Sladek FM, Sharrocks AD, Martins-Green M | title = MAP kinase phosphorylation-dependent activation of Elk-1 leads to activation of the co-activator p300 | journal = The EMBO Journal | volume = 22 | issue = 2 | pages = 281–291 | date = January 2003 | pmid = 12514134 | pmc = 140103 | doi = 10.1093/emboj/cdg028 }}</ref> An activated enhancer begins transcription of its RNA before activating transcription of messenger RNA from its target gene.<ref name="pmid32810208">{{cite journal | vauthors = Carullo NV, Phillips Iii RA, Simon RC, Soto SA, Hinds JE, Salisbury AJ, Revanna JS, Bunner KD, Ianov L, Sultan FA, Savell KE, Gersbach CA, Day JJ | title = Enhancer RNAs predict enhancer-gene regulatory links and are critical for enhancer function in neuronal systems | journal = Nucleic Acids Research | volume = 48 | issue = 17 | pages = 9550–9570 | date = September 2020 | pmid = 32810208 | pmc = 7515708 | doi = 10.1093/nar/gkaa671 }}</ref>