Editing Transcription (biology) (section)

====Enhancers, transcription factors, Mediator complex, and DNA loops in mammalian transcription====
[[File:Regulation of transcription in mammals.jpg|thumb|right|upright=2| '''Regulation of transcription in mammals'''. This illustration indicates many of the elements that are present when transcription of a gene is upregulated.]] 
[[Transcription preinitiation complex|Setting up]] for transcription in mammals is regulated by many [[cis-regulatory element]]s, including [[Promoter (genetics)|core promoter and promoter-proximal elements]] that are located near the [[Eukaryotic transcription|transcription start sites]] of genes. Core promoters combined with [[general transcription factor]]s are sufficient to direct transcription initiation, but generally have low basal activity.<ref name="pmid29946135">{{cite journal |vauthors=Haberle V, Stark A |title=Eukaryotic core promoters and the functional basis of transcription initiation |journal=Nat Rev Mol Cell Biol |volume=19 |issue=10 |pages=621–637 |date=October 2018 |pmid=29946135 |pmc=6205604 |doi=10.1038/s41580-018-0028-8 |url=}}</ref> 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=Front Cell Dev Biol |volume=8 |issue= |pages=592164 |date=2020 |pmid=33102493 |pmc=7554316 |doi=10.3389/fcell.2020.592164 |url=|doi-access=free }}</ref> Among this constellation of elements, enhancers and their associated [[transcription factors]] have a leading role in the initiation of gene transcription.<ref name="pmid22868264">{{cite journal |vauthors=Spitz F, Furlong EE |title=Transcription factors: from enhancer binding to developmental control |journal=Nat Rev Genet |volume=13 |issue=9 |pages=613–26 |date=September 2012 |pmid=22868264 |doi=10.1038/nrg3207 |s2cid=205485256 |url=}}</ref> An enhancer localized in a DNA region distant from the promoter of a gene can have a very large effect on gene transcription, with some genes undergoing up to 100-fold increased transcription due to an activated enhancer.<ref name=Beagan>{{cite journal |vauthors=Beagan JA, Pastuzyn ED, Fernandez LR, Guo MH, Feng K, Titus KR, Chandrashekar H, Shepherd JD, Phillips-Cremins JE |title=Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression |journal=Nat Neurosci |volume=23 |issue=6 |pages=707–717 |date=June 2020 |pmid=32451484 |pmc=7558717 |doi=10.1038/s41593-020-0634-6 |url=}}</ref>

Enhancers are regions of the genome that are major gene-regulatory elements. Enhancers control cell-type-specific gene transcription 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=Nat Rev Genet |volume=20 |issue=8 |pages=437–455 |date=August 2019 |pmid=31086298 |doi=10.1038/s41576-019-0128-0 |s2cid=152283312 |url=}}</ref> While there are hundreds of thousands of enhancer DNA regions,<ref name="pmid23503198">{{cite journal |vauthors=Pennacchio LA, Bickmore W, Dean A, Nobrega MA, Bejerano G |title=Enhancers: five essential questions |journal=Nat Rev Genet |volume=14 |issue=4 |pages=288–95 |date=April 2013 |pmid=23503198 |pmc=4445073 |doi=10.1038/nrg3458 |url=}}</ref> for a particular type of tissue only specific enhancers are brought into proximity with the promoters that they regulate. In a study of brain cortical neurons, 24,937 loops were found, bringing enhancers to their target promoters.<ref name=Beagan /> Multiple enhancers, each often at tens or hundred of thousands of nucleotides distant from their target genes, loop to their target gene promoters and can coordinate with each other to control transcription of their common target gene.<ref name=Schoenfelder />

The schematic illustration in this section shows an enhancer looping around to come into close physical 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]]), with one member of the dimer anchored to its binding motif on the enhancer and the other member 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=1573–88.e28 |date=December 2017 |pmid=29224777 |pmc=5785279 |doi=10.1016/j.cell.2017.11.008 |url=}}</ref> Several cell function specific transcription factors (there are 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 |url=|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=Proc Natl Acad Sci U S A |volume=115 |issue=30 |pages=E7222–30 |date=July 2018 |pmid=29987030 |pmc=6065035 |doi=10.1073/pnas.1804663115 |bibcode=2018PNAS..115E7222G |url=|doi-access=free }}</ref> and a small combination of these enhancer-bound transcription factors, when brought close to a promoter by a DNA loop, govern level of transcription of the target gene. [[Mediator (coactivator)|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=Nat Rev Mol Cell Biol |volume=16 |issue=3 |pages=155–66 |date=March 2015 |pmid=25693131 |pmc=4963239 |doi=10.1038/nrm3951 |url=}}</ref>

Enhancers, when active, are generally transcribed from both strands of DNA with RNA polymerases acting in two different directions, producing two [[enhancer RNA]]s (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 Dev |volume=32 |issue=1 |pages=42–57 |date=January 2018 |pmid=29378788 |pmc=5828394 |doi=10.1101/gad.308619.117 |url=}}</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=EMBO J |volume=22 |issue=2 |pages=281–91 |date=January 2003 |pmid=12514134 |pmc=140103 |doi=10.1093/emboj/cdg028 |url=}}</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 I 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 Res |volume=48 |issue=17 |pages=9550–70 |date=September 2020 |pmid=32810208 |pmc=7515708 |doi=10.1093/nar/gkaa671 |url=}}</ref>