Editing Transcription factor (section)

== Regulation ==

It is common in biology for important processes to have multiple layers of regulation and control.  This is also true with transcription factors:  Not only do transcription factors control the rates of transcription to regulate the amounts of gene products (RNA and protein) available to the cell but transcription factors themselves are regulated (often by other transcription factors).  Below is a brief synopsis of some of the ways that the activity of transcription factors can be regulated:

=== Synthesis ===

Transcription factors (like all proteins) are transcribed from a gene on a chromosome into RNA, and then the RNA is translated into protein.  Any of these steps can be regulated to affect the production (and thus activity) of a transcription factor. An implication of this is that transcription factors can regulate themselves. For example, in a [[negative feedback]] loop, the transcription factor acts as its own repressor:  If the transcription factor protein binds the DNA of its own gene, it down-regulates the production of more of itself.  This is one mechanism to maintain low levels of a transcription factor in a cell.<ref>{{Cite journal |vauthors=Pan G, Li J, Zhou Y, Zheng H, Pei D |date=August 2006 |title=A negative feedback loop of transcription factors that controls stem cell pluripotency and self-renewal |journal=FASEB Journal |volume=20 |issue=10 |pages=1730–2 |doi=10.1096/fj.05-5543fje |pmid=16790525 |s2cid=44783683 |doi-access=free}}</ref>

=== Nuclear localization ===

In [[eukaryote]]s, transcription factors (like most proteins) are transcribed in the [[Cell nucleus|nucleus]] but are then translated in the cell's [[cytoplasm]].  Many proteins that are active in the nucleus contain [[nuclear localization signal]]s that direct them to the nucleus.  But, for many transcription factors, this is a key point in their regulation.<ref name="pmid8314906">{{Cite journal |vauthors=Whiteside ST, Goodbourn S |date=April 1993 |title=Signal transduction and nuclear targeting: regulation of transcription factor activity by subcellular localisation |journal=Journal of Cell Science |volume=104 |issue=4 |pages=949–55 |doi=10.1242/jcs.104.4.949 |pmid=8314906}}</ref>  Important classes of transcription factors such as some [[nuclear receptor]]s must first bind a [[Ligand (biochemistry)|ligand]] while in the cytoplasm before they can relocate to the nucleus.<ref name="pmid8314906" />

=== Activation ===

Transcription factors may be activated (or deactivated) through their '''signal-sensing domain''' by a number of mechanisms including:
* [[ligand (biochemistry)|ligand]] binding – Not only is ligand binding able to influence where a transcription factor is located within a cell but ligand binding can also affect whether the transcription factor is in an active state and capable of binding DNA or other cofactors (see, for example, [[nuclear receptor]]s).
* [[phosphorylation]]<ref name="pmid2149275">{{Cite journal |vauthors=Bohmann D |date=November 1990 |title=Transcription factor phosphorylation: a link between signal transduction and the regulation of gene expression |journal=Cancer Cells |volume=2 |issue=11 |pages=337–44 |pmid=2149275}}</ref><ref name="pmid17536004">{{Cite journal |vauthors=Weigel NL, Moore NL |date=October 2007 |title=Steroid receptor phosphorylation: a key modulator of multiple receptor functions |journal=Molecular Endocrinology |volume=21 |issue=10 |pages=2311–9 |doi=10.1210/me.2007-0101 |pmid=17536004 |doi-access=free}}</ref> – Many transcription factors such as [[STAT protein]]s must be [[phosphorylation|phosphorylated]] before they can bind DNA.
* interaction with other transcription factors (''e.g.'', homo- or hetero-[[protein dimer|dimerization]]) or [[transcription coregulator|coregulatory]] proteins{{cn|date=March 2024}}

=== Accessibility of DNA-binding site ===

In eukaryotes, DNA is organized with the help of [[histone]]s into compact particles called [[nucleosome]]s, where sequences of about 147 DNA base pairs make ~1.65 turns around histone protein octamers. DNA within nucleosomes is inaccessible to many transcription factors. Some transcription factors, so-called [[pioneer factor]]s are still able to bind their DNA binding sites on the nucleosomal DNA. For most other transcription factors, the nucleosome should be actively unwound by molecular motors such as [[Chromatin remodeling|chromatin remodelers]].<ref>{{Cite journal |vauthors=Teif VB, Rippe K |date=September 2009 |title=Predicting nucleosome positions on the DNA: combining intrinsic sequence preferences and remodeler activities |journal=Nucleic Acids Research |volume=37 |issue=17 |pages=5641–55 |doi=10.1093/nar/gkp610 |pmc=2761276 |pmid=19625488}}</ref> Alternatively, the nucleosome can be partially unwrapped by thermal fluctuations, allowing temporary access to the transcription factor binding site. In many cases, a transcription factor needs to [[Competitive inhibition|compete for binding]] to its DNA binding site with other transcription factors and histones or non-histone chromatin proteins.<ref>{{Cite journal |vauthors=Teif VB, Rippe K |date=October 2010 |title=Statistical-mechanical lattice models for protein-DNA binding in chromatin |journal=Journal of Physics: Condensed Matter |volume=22 |issue=41 |pages=414105 |arxiv=1004.5514 |bibcode=2010JPCM...22O4105T |doi=10.1088/0953-8984/22/41/414105 |pmid=21386588 |s2cid=103345}}</ref>  Pairs of transcription factors and other proteins can play antagonistic roles (activator versus repressor) in the regulation of the same [[gene]].{{cn|date=March 2024}}

=== Availability of other cofactors/transcription factors ===

Most transcription factors do not work alone.  Many large TF families form complex homotypic or heterotypic interactions through dimerization.<ref>{{Cite journal |vauthors=Amoutzias GD, Robertson DL, Van de Peer Y, Oliver SG |date=May 2008 |title=Choose your partners: dimerization in eukaryotic transcription factors |journal=Trends in Biochemical Sciences |volume=33 |issue=5 |pages=220–9 |doi=10.1016/j.tibs.2008.02.002 |pmid=18406148}}</ref> For gene transcription to occur, a number of transcription factors must bind to DNA regulatory sequences.  This collection of transcription factors, in turn, recruit intermediary proteins such as [[transcription coregulator|cofactors]] that allow efficient recruitment of the [[Transcription preinitiation complex|preinitiation complex]] and [[RNA polymerase]].  Thus, for a single transcription factor to initiate transcription, all of these other proteins must also be present, and the transcription factor must be in a state where it can bind to them if necessary.
Cofactors are proteins that modulate the effects of transcription factors. Cofactors are interchangeable between specific gene promoters; the protein complex that occupies the promoter DNA and the amino acid sequence of the cofactor determine its spatial conformation. For example, certain steroid receptors can exchange cofactors with [[NF-κB]], which is a switch between inflammation and cellular differentiation; thereby steroids can affect the inflammatory response and function of certain tissues.<ref>{{Cite journal |vauthors=Copland JA, Sheffield-Moore M, Koldzic-Zivanovic N, Gentry S, Lamprou G, Tzortzatou-Stathopoulou F, Zoumpourlis V, Urban RJ, Vlahopoulos SA |date=June 2009 |title=Sex steroid receptors in skeletal differentiation and epithelial neoplasia: is tissue-specific intervention possible? |journal=BioEssays |volume=31 |issue=6 |pages=629–41 |doi=10.1002/bies.200800138 |pmid=19382224 |s2cid=205469320}}</ref>

=== 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]]).