Editing Transcription factor (section)

=== Interaction with methylated cytosine ===

Transcription factors and methylated cytosines in DNA both have major roles in regulating gene expression.  (Methylation of cytosine in DNA primarily occurs where cytosine is followed by guanine in the 5' to 3' DNA sequence, a [[CpG site]].)  Methylation of CpG sites in a promoter region of a gene usually represses gene transcription,<ref name="pmid17334365">{{Cite journal |vauthors=Weber M, Hellmann I, Stadler MB, Ramos L, Pääbo S, Rebhan M, Schübeler D |date=April 2007 |title=Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome |journal=Nat. Genet. |volume=39 |issue=4 |pages=457–66 |doi=10.1038/ng1990 |pmid=17334365 |s2cid=22446734}}</ref> while methylation of CpGs in the body of a gene increases expression.<ref name="pmid25263941">{{Cite journal |vauthors=Yang X, Han H, De Carvalho DD, Lay FD, Jones PA, Liang G |date=October 2014 |title=Gene body methylation can alter gene expression and is a therapeutic target in cancer |journal=Cancer Cell |volume=26 |issue=4 |pages=577–90 |doi=10.1016/j.ccr.2014.07.028 |pmc=4224113 |pmid=25263941}}</ref>  [[TET enzymes]] play a central role in demethylation of methylated cytosines.  Demethylation of CpGs in a gene promoter by TET enzyme activity increases transcription of the gene.<ref name="pmid24108092">{{Cite journal |vauthors=Maeder ML, Angstman JF, Richardson ME, Linder SJ, Cascio VM, Tsai SQ, Ho QH, Sander JD, Reyon D, Bernstein BE, Costello JF, Wilkinson MF, Joung JK |date=December 2013 |title=Targeted DNA demethylation and activation of endogenous genes using programmable TALE-TET1 fusion proteins |journal=Nat. Biotechnol. |volume=31 |issue=12 |pages=1137–42 |doi=10.1038/nbt.2726 |pmc=3858462 |pmid=24108092}}</ref>

The [[DNA binding site]]s of 519 transcription factors were evaluated.<ref name="pmid28473536">{{Cite journal |vauthors=Yin Y, Morgunova E, Jolma A, Kaasinen E, Sahu B, Khund-Sayeed S, Das PK, Kivioja T, Dave K, Zhong F, Nitta KR, Taipale M, Popov A, Ginno PA, Domcke S, Yan J, Schübeler D, Vinson C, Taipale J |date=May 2017 |title=Impact of cytosine methylation on DNA binding specificities of human transcription factors |journal=Science |volume=356 |issue=6337 |pages=eaaj2239 |doi=10.1126/science.aaj2239 |pmc=8009048 |pmid=28473536 |s2cid=206653898}}</ref>   Of these, 169 transcription factors (33%) did not have CpG dinucleotides in their binding sites, and 33 transcription factors (6%) could bind to a CpG-containing motif but did not display a preference for a binding site with either a methylated or unmethylated CpG.  There were 117 transcription factors (23%) that were inhibited from binding to their binding sequence if it contained a methylated CpG site, 175 transcription factors (34%) that had enhanced binding if their binding sequence had a methylated CpG site, and 25 transcription factors (5%) were either inhibited or had enhanced binding depending on where in the binding sequence the methylated CpG was located.{{cn|date=March 2024}}

TET enzymes do not specifically bind to methylcytosine except when recruited (see [[DNA demethylation]]).  Multiple transcription factors important in cell differentiation and lineage specification, including [[Homeobox protein NANOG|NANOG]], [[SALL4]]A, [[WT1]], [[EBF1]], [[SPI1|PU.1]], and [[TCF3|E2A]], have been shown to recruit TET enzymes to specific genomic loci (primarily enhancers) to act on methylcytosine (mC) and convert it to hydroxymethylcytosine hmC (and in most cases marking them for subsequent complete demethylation to cytosine).<ref name="pmid30809228">{{Cite journal |vauthors=Lio CJ, Rao A |year=2019 |title=TET Enzymes and 5hmC in Adaptive and Innate Immune Systems |journal=Front Immunol |volume=10 |pages=210 |doi=10.3389/fimmu.2019.00210 |pmc=6379312 |pmid=30809228 |doi-access=free}}</ref>  TET-mediated conversion of mC to hmC appears to disrupt the binding of 5mC-binding proteins including [[MECP2]] and MBD ([[Methyl-CpG-binding domain]]) proteins, facilitating nucleosome remodeling and the binding of transcription factors, thereby activating transcription of those genes.  [[EGR1]] is an important transcription factor in [[memory]] formation.  It has an essential role in [[brain]] [[neuron]] [[epigenetics|epigenetic]] reprogramming.  The transcription factor [[EGR1]] recruits the [[Tet methylcytosine dioxygenase 1|TET1]] protein that initiates a pathway of [[DNA demethylation]].<ref>Sun Z, Xu X, He J, Murray A, Sun MA, Wei X, Wang X, McCoig E, Xie E, Jiang X, Li L, Zhu J, Chen J, Morozov A, Pickrell AM, Theus MH, Xie H.  EGR1 recruits TET1 to shape the brain methylome during development and upon neuronal activity.  Nat Commun. 2019 Aug 29;10(1):3892. doi: 10.1038/s41467-019-11905-3.  PMID 31467272</ref>  EGR1, together with TET1, is employed in programming the distribution of methylation sites on brain DNA during brain development and in [[learning]] (see [[Epigenetics in learning and memory]]).