View source for Transcription factor

{{Short description|Protein that regulates the rate of DNA transcription}}
{{Use dmy dates|date=March 2022}}
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{{Transcription factor glossary}}
[[File:Transcription Factors.svg|thumb|upright=1.75|Illustration of an activator]]

In [[molecular biology]], a '''transcription factor''' ('''TF''') (or '''sequence-specific DNA-binding factor''') is a [[protein]] that controls the rate of [[transcription (genetics)|transcription]] of [[genetics|genetic]] information from [[DNA]] to [[messenger RNA]], by binding to a specific [[DNA sequence]].<ref name="pmid9570129">{{Cite journal |vauthors=Latchman DS |date=December 1997 |title=Transcription factors: an overview |journal=The International Journal of Biochemistry & Cell Biology |volume=29 |issue=12 |pages=1305–12 |doi=10.1016/S1357-2725(97)00085-X |pmc=2002184 |pmid=9570129}}</ref><ref name="pmid2128034">{{Cite journal |vauthors=Karin M |date=February 1990 |title=Too many transcription factors: positive and negative interactions |journal=The New Biologist |volume=2 |issue=2 |pages=126–31 |pmid=2128034}}</ref> The function of TFs is to regulate—turn on and off—genes in order to make sure that they are [[Gene expression|expressed]] in the desired [[Cell (biology)|cells]] at the right time and in the right amount throughout the life of the cell and the organism. Groups of TFs function in a coordinated fashion to direct [[cell division]], [[cell growth]], and [[cell death]] throughout life; [[cell migration]] and organization ([[body plan]]) during embryonic development; and intermittently in response to signals from outside the cell, such as a [[hormone]].  There are approximately 1600 TFs in the [[human genome]], where half of them are [[C2H2 zinc-finger|C2H2 zinc fingers]].<ref name="pmid15193307">{{Cite journal |vauthors=Babu MM, Luscombe NM, Aravind L, Gerstein M, Teichmann SA |date=June 2004 |title=Structure and evolution of transcriptional regulatory networks |url=http://www.mrc-lmb.cam.ac.uk/genomes/madanm/chalancon_chapter.pdf |journal=Current Opinion in Structural Biology |volume=14 |issue=3 |pages=283–91 |doi=10.1016/j.sbi.2004.05.004 |pmid=15193307 |archive-url=https://web.archive.org/web/20190830175950/https://www.mrc-lmb.cam.ac.uk/genomes/madanm/chalancon_chapter.pdf |archive-date=30 August 2019 |access-date=25 October 2017}}</ref><ref name="Lyons">{{YouTube |title= How Genes are Regulated: Transcription Factors |id=MkUgkDLp2iE|time=2m16s}}</ref><ref name=":3">{{Cite journal |vauthors=Lambert S, Jolma A, Campitelli L, Pratyush Z, Das K, Yin Y, Albu M, Chen X, Taipae J, Hughes T, Weirauch M |year=2018 |title=The Human Transcription Factors |journal=Cell |volume=172 |issue=4 |pages=650–665 |doi=10.1016/j.cell.2018.01.029 |pmid=29425488 |quote=The final tally encompasses 1,639 known or likely human TFs. |doi-access=free}}</ref><ref name=":2">{{Cite journal |last1=Lambert |first1=Samuel A. |last2=Jolma |first2=Arttu |last3=Campitelli |first3=Laura F. |last4=Das |first4=Pratyush K. |last5=Yin |first5=Yimeng |last6=Albu |first6=Mihai |last7=Chen |first7=Xiaoting |last8=Taipale |first8=Jussi |last9=Hughes |first9=Timothy R. |last10=Weirauch |first10=Matthew T. |date=2018-02-08 |title=The Human Transcription Factors |url=https://www.cell.com/cell/abstract/S0092-8674(18)30106-5 |journal=Cell |language=English |volume=172 |issue=4 |pages=650–665 |doi=10.1016/j.cell.2018.01.029 |issn=0092-8674 |pmid=29425488}}</ref> Transcription factors are members of the [[proteome]] as well as [[regulome]].

TFs work alone or with other proteins in a complex, by promoting (as an [[Activator (genetics)|activator]]), or blocking (as a [[repressor]]) the recruitment of [[RNA polymerase]] (the enzyme that performs the [[transcription (genetics)|transcription]] of genetic information from DNA to RNA) to specific genes.<ref name="pmid8870495">{{Cite journal |vauthors=Roeder RG |date=September 1996 |title=The role of general initiation factors in transcription by RNA polymerase II |journal=Trends in Biochemical Sciences |volume=21 |issue=9 |pages=327–35 |doi=10.1016/S0968-0004(96)10050-5 |pmid=8870495}}</ref><ref name="pmid8990153">{{Cite journal |vauthors=Nikolov DB, Burley SK |date=January 1997 |title=RNA polymerase II transcription initiation: a structural view |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=94 |issue=1 |pages=15–22 |bibcode=1997PNAS...94...15N |doi=10.1073/pnas.94.1.15 |pmc=33652 |pmid=8990153 |doi-access=free}}</ref><ref name="pmid11092823">{{Cite journal |vauthors=Lee TI, Young RA |year=2000 |title=Transcription of eukaryotic protein-coding genes |journal=Annual Review of Genetics |volume=34 |pages=77–137 |doi=10.1146/annurev.genet.34.1.77 |pmid=11092823}}</ref>

A defining feature of TFs is that they contain at least one [[DNA-binding domain]] (DBD), which attaches to a specific sequence of DNA adjacent to the genes that they regulate.<ref name="pmid2667136">{{Cite journal |vauthors=Mitchell PJ, Tjian R |date=July 1989 |title=Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins |journal=Science |volume=245 |issue=4916 |pages=371–8 |bibcode=1989Sci...245..371M |doi=10.1126/science.2667136 |pmid=2667136}}</ref><ref name="pmid9121580">{{Cite journal |vauthors=Ptashne M, Gann A |date=April 1997 |title=Transcriptional activation by recruitment |journal=Nature |volume=386 |issue=6625 |pages=569–77 |bibcode=1997Natur.386..569P |doi=10.1038/386569a0 |pmid=9121580 |s2cid=6203915}}</ref>  TFs are grouped into classes based on their DBDs.<ref name="Jin_2014">{{Cite journal |vauthors=Jin J, Zhang H, Kong L, Gao G, Luo J |date=January 2014 |title=PlantTFDB 3.0: a portal for the functional and evolutionary study of plant transcription factors |journal=Nucleic Acids Research |volume=42 |issue=Database issue |pages=D1182-7 |doi=10.1093/nar/gkt1016 |pmc=3965000 |pmid=24174544}}</ref><ref name="Matys_2006" /> Other proteins such as [[coactivator (genetics)|coactivators]], [[Chromatin Structure Remodeling (RSC) Complex|chromatin remodelers]], [[histone acetyltransferase]]s, [[histone deacetylase]]s, [[kinase]]s, and [[methylase]]s are also essential to gene regulation, but lack DNA-binding domains, and therefore are not TFs.<ref name="pmid11823631">{{Cite journal |vauthors=Brivanlou AH, Darnell JE |date=February 2002 |title=Signal transduction and the control of gene expression |journal=Science |volume=295 |issue=5556 |pages=813–8 |bibcode=2002Sci...295..813B |doi=10.1126/science.1066355 |pmid=11823631 |s2cid=14954195}}</ref>

TFs are of interest in medicine because TF mutations can cause specific diseases, and medications can be potentially targeted toward them.

== Number ==
{{main listing|List of human transcription factors|more=no}}
Transcription factors are essential for the regulation of gene expression and are, as a consequence, found in all living organisms. The number of transcription factors found within an organism increases with genome size, and larger genomes tend to have more transcription factors per gene.<ref name="pmid12957540">{{Cite journal |vauthors=van Nimwegen E |date=September 2003 |title=Scaling laws in the functional content of genomes |journal=Trends in Genetics |volume=19 |issue=9 |pages=479–84 |arxiv=physics/0307001 |doi=10.1016/S0168-9525(03)00203-8 |pmid=12957540 |s2cid=15887416}}</ref>

There are approximately 2800 proteins in the [[human genome]] that contain DNA-binding domains, and 1600 of these are presumed to function as transcription factors,<ref name="pmid15193307" /> where half of them (~800) are C2H2 zinc finger proteins.<ref name=":2" /> Therefore, approximately 10% of genes in the genome code for transcription factors, which makes this family the single largest family of human proteins.  Furthermore, genes are often flanked by several binding sites for distinct transcription factors, and efficient expression of each of these genes requires the cooperative action of several different transcription factors (see, for example, [[hepatocyte nuclear factors#Function|hepatocyte nuclear factors]]).  Hence, the combinatorial use of a subset of the approximately 2000 human transcription factors easily accounts for the unique regulation of each gene in the human genome during [[developmental biology|development]].<ref name="pmid11823631" />

== Mechanism ==
Transcription factors bind to either [[enhancer (genetics)|enhancer]] or [[promoter (biology)|promoter]] regions of DNA adjacent to the genes that they regulate based on recognizing specific DNA motifs.  Depending on the transcription factor, the transcription of the adjacent gene is either [[Downregulation and upregulation|up- or down-regulated]].  Transcription factors use a variety of mechanisms for the regulation of gene expression.<ref name="pmid11758455">{{Cite journal |vauthors=Gill G |year=2001 |title=Regulation of the initiation of eukaryotic transcription |journal=Essays in Biochemistry |volume=37 |pages=33–43 |doi=10.1042/bse0370033 |pmid=11758455}}</ref>  These mechanisms include:
* stabilize or block the binding of RNA polymerase to DNA{{citation needed|date=March 2024}}
* catalyze the [[acetylation]] or deacetylation of [[histone]] proteins.  The transcription factor can either do this directly or recruit other proteins with this catalytic activity.  Many transcription factors use one or the other of two opposing mechanisms to regulate transcription:<ref name="pmid11909519">{{Cite journal |vauthors=Narlikar GJ, Fan HY, Kingston RE |date=February 2002 |title=Cooperation between complexes that regulate chromatin structure and transcription |journal=Cell |volume=108 |issue=4 |pages=475–87 |doi=10.1016/S0092-8674(02)00654-2 |pmid=11909519 |s2cid=14586791 |doi-access=free}}</ref>
** [[histone acetyltransferase]] (HAT) activity – acetylates [[histone]] proteins, which weakens the association of DNA with [[histone]]s, which make the DNA more accessible to transcription, thereby up-regulating transcription
** [[histone deacetylase]] (HDAC) activity – deacetylates [[histone]] proteins, which strengthens the association of DNA with histones, which make the DNA less accessible to transcription, thereby down-regulating transcription
* recruit [[coactivator (genetics)|coactivator]] or [[corepressor (genetics)|corepressor]] proteins to the transcription factor DNA complex<ref name="pmid10322133">{{Cite journal |vauthors=Xu L, Glass CK, Rosenfeld MG |date=April 1999 |title=Coactivator and corepressor complexes in nuclear receptor function |journal=Current Opinion in Genetics & Development |volume=9 |issue=2 |pages=140–7 |doi=10.1016/S0959-437X(99)80021-5 |pmid=10322133}}</ref>

== Function ==

Transcription factors are one of the groups of proteins that read and interpret the genetic "blueprint" in the DNA.  They bind to the DNA and help initiate a program of increased or decreased gene transcription.  As such, they are vital for many important cellular processes.  Below are some of the important functions and biological roles transcription factors are involved in:

=== Basal transcriptional regulation ===

In [[eukaryote]]s, an important class of transcription factors called [[general transcription factor]]s (GTFs) are necessary for transcription to occur.<ref name="isbn1-86094-126-5">{{Cite book | vauthors = Weinzierl RO |url=https://archive.org/details/mechanismsofgene0000wein |title=Mechanisms of Gene Expression: Structure, Function and Evolution of the Basal Transcriptional Machinery |publisher=World Scientific Publishing Company |year=1999 |isbn=1-86094-126-5 |url-access=registration}}</ref><ref name="pmid12672487">{{Cite journal |vauthors=Reese JC |date=April 2003 |title=Basal transcription factors |journal=Current Opinion in Genetics & Development |volume=13 |issue=2 |pages=114–8 |doi=10.1016/S0959-437X(03)00013-3 |pmid=12672487}}</ref><ref name="pmid12676794">{{Cite journal |vauthors=Shilatifard A, Conaway RC, Conaway JW |year=2003 |title=The RNA polymerase II elongation complex |journal=Annual Review of Biochemistry |volume=72 |pages=693–715 |doi=10.1146/annurev.biochem.72.121801.161551 |pmid=12676794}}</ref>  Many of these GTFs do not actually bind DNA, but rather are part of the large [[transcription preinitiation complex]] that interacts with [[RNA polymerase]] directly.  The most common GTFs are [[TFIIA]], [[TFIIB]], [[TFIID]] (see also [[TATA binding protein]]), [[TFIIE]], [[TFIIF]], and [[TFIIH]].<ref name="pmid16858867">{{Cite journal |vauthors=Thomas MC, Chiang CM |year=2006 |title=The general transcription machinery and general cofactors |journal=Critical Reviews in Biochemistry and Molecular Biology |volume=41 |issue=3 |pages=105–78 |doi=10.1080/10409230600648736 |pmid=16858867 |s2cid=13073440}}</ref>  The preinitiation complex binds to [[promotor (biology)|promoter]] regions of DNA upstream to the gene that they regulate.

=== Differential enhancement of transcription ===
Other transcription factors differentially regulate the expression of various genes by binding to [[enhancer (genetics)|enhancer]] regions of DNA adjacent to regulated genes.  These transcription factors are critical to making sure that genes are expressed in the right cell at the right time and in the right amount, depending on the changing requirements of the organism.{{citation needed|date=March 2024}}

==== Development ====

Many transcription factors in [[multicellular organism]]s are involved in development.<ref name="pmid1424766">{{Cite book |title=Transcription factors and mammalian development |vauthors=Lobe CG |year=1992 |isbn=978-0-12-153127-0 |series=Current Topics in Developmental Biology |volume=27 |pages=351–83 |doi=10.1016/S0070-2153(08)60539-6 |pmid=1424766}}</ref>  Responding to stimuli, these transcription factors turn on/off the transcription of the appropriate genes, which, in turn, allows for changes in cell [[morphology (biology)|morphology]] or activities needed for [[cell fate determination]] and [[cellular differentiation]].  The [[Hox (gene)|Hox]] transcription factor family, for example, is important for proper [[Regional specification|body pattern formation]] in organisms as diverse as fruit flies to humans.<ref name="pmid17008523">{{Cite journal |vauthors=Lemons D, McGinnis W |date=September 2006 |title=Genomic evolution of Hox gene clusters |journal=Science |volume=313 |issue=5795 |pages=1918–22 |bibcode=2006Sci...313.1918L |doi=10.1126/science.1132040 |pmid=17008523 |s2cid=35650754}}</ref><ref name="pmid16515781">{{Cite journal |author-link=Cecilia Moens |vauthors=Moens CB, Selleri L |date=March 2006 |title=Hox cofactors in vertebrate development |journal=Developmental Biology |volume=291 |issue=2 |pages=193–206 |doi=10.1016/j.ydbio.2005.10.032 |pmid=16515781 |doi-access=free}}</ref>  Another example is the transcription factor encoded by the [[SRY|sex-determining region Y]] (SRY) gene, which plays a major role in determining sex in humans.<ref name="pmid17187356">{{Cite journal |vauthors=Ottolenghi C, Uda M, Crisponi L, Omari S, Cao A, Forabosco A, Schlessinger D |date=January 2007 |title=Determination and stability of sex |journal=BioEssays |volume=29 |issue=1 |pages=15–25 |doi=10.1002/bies.20515 |pmid=17187356 |hdl=11380/611683 |s2cid=23824870|hdl-access=free }}</ref>

==== Response to intercellular signals ====

Cells can communicate with each other by releasing molecules that produce [[signal transduction|signaling cascades]] within another receptive cell.  If the signal requires upregulation or downregulation of genes in the recipient cell, often transcription factors will be downstream in the signaling cascade.<ref name="pmid8293575">{{Cite journal |vauthors=Pawson T |year=1993 |title=Signal transduction--a conserved pathway from the membrane to the nucleus |journal=Developmental Genetics |volume=14 |issue=5 |pages=333–8 |doi=10.1002/dvg.1020140502 |pmid=8293575}}</ref> [[Estrogen]] signaling is an example of a fairly short signaling cascade that involves the [[estrogen receptor]] transcription factor:  Estrogen is secreted by tissues such as the [[ovary|ovaries]] and [[placenta]], crosses the [[cell membrane]] of the recipient cell, and is bound by the estrogen receptor in the cell's [[cytoplasm]].  The estrogen receptor then goes to the cell's [[Cell nucleus|nucleus]] and binds to its [[DNA binding site|DNA-binding sites]], changing the transcriptional regulation of the associated genes.<ref name="pmid11916222">{{Cite journal |vauthors=Osborne CK, Schiff R, Fuqua SA, Shou J |date=December 2001 |title=Estrogen receptor: current understanding of its activation and modulation |journal=Clinical Cancer Research |volume=7 |issue=12 Suppl |pages=4338s–4342s; discussion 4411s–4412s |pmid=11916222}}</ref>

==== Response to environment ====

Not only do transcription factors act downstream of signaling cascades related to biological stimuli but they can also be downstream of signaling cascades involved in environmental stimuli.  Examples include [[heat shock factor]] (HSF), which upregulates genes necessary for survival at higher temperatures,<ref name="pmid18239856">{{Cite journal |vauthors=Shamovsky I, Nudler E |date=March 2008 |title=New insights into the mechanism of heat shock response activation |journal=Cellular and Molecular Life Sciences |volume=65 |issue=6 |pages=855–61 |doi=10.1007/s00018-008-7458-y |pmc=11131843 |pmid=18239856 |s2cid=9912334}}</ref> [[hypoxia inducible factor]] (HIF), which upregulates genes necessary for cell survival in low-oxygen environments,<ref name="pmid18202826">{{Cite journal |vauthors=Benizri E, Ginouvès A, Berra E |date=April 2008 |title=The magic of the hypoxia-signaling cascade |journal=Cellular and Molecular Life Sciences |volume=65 |issue=7–8 |pages=1133–49 |doi=10.1007/s00018-008-7472-0 |pmc=11131810 |pmid=18202826 |s2cid=44049779}}</ref> and [[sterol regulatory element binding protein]] (SREBP), which helps maintain proper [[lipid]] levels in the cell.<ref name="pmid15457548">{{Cite journal |vauthors=Weber LW, Boll M, Stampfl A |date=November 2004 |title=Maintaining cholesterol homeostasis: sterol regulatory element-binding proteins |journal=World Journal of Gastroenterology |volume=10 |issue=21 |pages=3081–7 |doi=10.3748/wjg.v10.i21.3081 |pmc=4611246 |pmid=15457548 |doi-access=free}}</ref>

==== Cell cycle control ====

Many transcription factors, especially some that are [[proto-oncogene]]s or [[tumor suppressor gene|tumor suppressors]], help regulate the [[cell cycle]] and as such determine how large a cell will get and when it can divide into two daughter cells.<ref name="pmid8960358">{{Cite journal |vauthors=Wheaton K, Atadja P, Riabowol K |year=1996 |title=Regulation of transcription factor activity during cellular aging |journal=Biochemistry and Cell Biology |volume=74 |issue=4 |pages=523–34 |doi=10.1139/o96-056 |pmid=8960358 |bibcode=1996BCB....74..523W }}</ref><ref name="pmid8864058">{{Cite journal |vauthors=Meyyappan M, Atadja PW, Riabowol KT |year=1996 |title=Regulation of gene expression and transcription factor binding activity during cellular aging |journal=Biological Signals |volume=5 |issue=3 |pages=130–8 |doi=10.1159/000109183 |pmid=8864058}}</ref>  One example is the [[Myc]] oncogene, which has important roles in [[cell growth]] and [[apoptosis]].<ref name="pmid7846125">{{Cite journal |vauthors=Evan G, Harrington E, Fanidi A, Land H, Amati B, Bennett M |date=August 1994 |title=Integrated control of cell proliferation and cell death by the c-myc oncogene |journal=Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences |volume=345 |issue=1313 |pages=269–75 |bibcode=1994RSPTB.345..269E |doi=10.1098/rstb.1994.0105 |pmid=7846125}}</ref>

==== Pathogenesis ====

Transcription factors can also be used to alter gene expression in a host cell to promote pathogenesis.  A well studied example of this are the transcription-activator like effectors ([[TAL effector]]s) secreted by [[Xanthomonas]] bacteria.  When injected into plants, these proteins can enter the nucleus of the plant cell, bind plant promoter sequences, and activate transcription of plant genes that aid in bacterial infection.<ref name="Boch J, Bonas U. 2010">{{Cite journal |vauthors=Boch J, Bonas U |year=2010 |title=Xanthomonas AvrBs3 family-type III effectors: discovery and function |journal=Annual Review of Phytopathology |volume=48 |issue=1 |pages=419–36 |doi=10.1146/annurev-phyto-080508-081936 |pmid=19400638|bibcode=2010AnRvP..48..419B }}</ref> TAL effectors contain a central repeat region in which there is a simple relationship between the identity of two critical residues in sequential repeats and sequential DNA bases in the TAL effector's target site.<ref name="Moscou2010">{{Cite journal |vauthors=Moscou MJ, Bogdanove AJ |date=December 2009 |title=A simple cipher governs DNA recognition by TAL effectors |journal=Science |volume=326 |issue=5959 |page=1501 |bibcode=2009Sci...326.1501M |doi=10.1126/science.1178817 |pmid=19933106 |s2cid=6648530}}</ref><ref name="Boch J, Scholze H, Schornack S, ''et al.'' 2010">{{Cite journal |vauthors=Boch J, Scholze H, Schornack S, Landgraf A, Hahn S, Kay S, Lahaye T, Nickstadt A, Bonas U |date=December 2009 |title=Breaking the code of DNA binding specificity of TAL-type III effectors |journal=Science |volume=326 |issue=5959 |pages=1509–12 |bibcode=2009Sci...326.1509B |doi=10.1126/science.1178811 |pmid=19933107 |s2cid=206522347}}</ref> This property likely makes it easier for these proteins to evolve in order to better compete with the defense mechanisms of the host cell.<ref name="Voytas DF, Joung JK. 2010.">{{Cite journal |vauthors=Voytas DF, Joung JK |date=December 2009 |title=Plant science. DNA binding made easy |journal=Science |volume=326 |issue=5959 |pages=1491–2 |bibcode=2009Sci...326.1491V |doi=10.1126/science.1183604 |pmc=7814878 |pmid=20007890 |s2cid=33257689}}</ref>

== 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 or effector domains. However, not all transcription factors have an effector domain; for example, approximately 400 C2H2 zinc finger transcription factors contain only DNA-binding domains (DBDs).<ref name=":3" /> Activation or repression of transcription factors can occur through 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]]) 
* interacting with [[transcription coregulator|coregulatory]] proteins such as co-activators (e.g., [[COP9 constitutive photomorphogenic homolog subunit 5|COPS5]], [[EP300]], [[BCL3]]); co-repressors (e.g., [[Nuclear receptor co-repressor 1|NCOR1]], [[SIN3A]], [[TRIM24]]). However, there are [[Transcription coregulator|transcription co-regulators]] that can act as both, activator and repressors.

=== 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 |article-number=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]].{{citation needed|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 |article-number=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.{{citation needed|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 |article-number=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]]).

== Structure ==
[[File:Transcription factor schematic 2.png|thumb|upright=1.75|Schematic diagram of the amino acid sequence (amino terminus to the left and carboxylic acid terminus to the right) of a prototypical transcription factor that contains (1) a DNA-binding domain (DBD), (2) signal-sensing domain (SSD), and Activation domain (AD). The order of placement and the number of domains may differ in various types of transcription factors. In addition, the transactivation and signal-sensing functions are frequently contained within the same domain.]]

[[File:LacI Dimer Structure Annotated.png|thumb|upright=1.25|'''Domain architecture example: [[lac repressor|Lactose Repressor (LacI)]]'''.  The N-terminal DNA binding domain (labeled) of the [[lac repressor|''lac'' repressor]] binds its target DNA sequence (gold) in the major groove using a [[helix-turn-helix]] motif. Effector molecule binding (green) occurs in the regulatory domain (labeled).  This triggers an allosteric response mediated by the linker region (labeled).]]

Transcription factors are modular in structure and contain the following [[protein domains|domains]]:<ref name="pmid9570129" />
* '''[[DNA-binding domain]]''' ('''DBD'''), which attaches to specific sequences of DNA ([[enhancer (genetics)|enhancer]] or [[promoter (biology)|promoter]]. Necessary component for all vectors. Used to drive transcription of the vector's transgene [[promoter (biology)|promoter]] sequences) adjacent to regulated genes.  DNA sequences that bind transcription factors are often referred to as '''[[hormone response element|response elements]]'''. Sometimes, DBDs can directly recruit transcription coregulators<ref>{{Cite journal |last1=Bianchi |first1=Daniëlle |last2=Borza |first2=Razvan |last3=De Zan |first3=Erica |last4=Huelsz-Prince |first4=Guizela |last5=Gregoricchio |first5=Sebastian |last6=Dekker |first6=Marleen |last7=Fish |first7=Alex |last8=Mazouzi |first8=Abdelghani |last9=Kroese |first9=Lona J. |last10=Linder |first10=Simon |last11=Hernandez-Quiles |first11=Miguel |last12=Vermeulen |first12=Michiel |last13=Celie |first13=Patrick H. N. |last14=Krimpenfort |first14=Paul |last15=Song |first15=Ji-Ying |date=2025-07-03 |title=Zincore, an atypical coregulator, binds zinc finger transcription factors to control gene expression |url=https://www.science.org/doi/10.1126/science.adv2861 |journal=Science |language=en |volume=389 |issue=6755 |article-number=eadv2861 |doi=10.1126/science.adv2861 |pmid=40608935 |bibcode=2025Sci...389v2861B |issn=0036-8075|url-access=subscription }}</ref> without the need of an activation domain.
* '''[[Trans-activating domain|Activation domain]]''' ('''AD'''), which contains binding sites for other proteins such as [[transcription coregulator]]s.  These binding sites are frequently referred to as '''activation functions''' ('''AFs'''), '''Transactivation domain''' ('''TAD''') or '''Trans-activating domain''' [[Trans-activating domain|TAD]], not to be confused with topologically associating domain ([[Topologically associating domain|TAD]]).<ref name="pmid12893880">{{Cite journal |vauthors=Wärnmark A, Treuter E, Wright AP, Gustafsson JA |date=October 2003 |title=Activation functions 1 and 2 of nuclear receptors: molecular strategies for transcriptional activation |journal=Molecular Endocrinology |volume=17 |issue=10 |pages=1901–9 |doi=10.1210/me.2002-0384 |pmid=12893880 |s2cid=31314461 |doi-access=free}}</ref> However, not all TFs have a activation domain (e.g., half of them (~800) are C2H2 zinc finger proteins)<ref name=":3" />
*  An optional '''signal-sensing domain''' ('''SSD''') (''e.g.'', a ligand-binding domain), which senses external signals and, in response, transmits these signals to the rest of the transcription complex, resulting in up- or down-regulation of gene expression.  Also, the DBD and signal-sensing domains may reside on separate proteins that associate within the transcription complex to regulate gene expression.

=== DNA-binding domain ===
[[File:Transcription factors DNA binding sites.svg|thumb|right|DNA contacts of different types of [[w:DNA-binding domain|DNA-binding domains]] of transcription factors]]

{{Main|DNA-binding domain}}
The portion ([[protein domains|domain]]) of the transcription factor that binds DNA is called its DNA-binding domain.  Below is a partial list of some of the major families of DNA-binding domains/transcription factors:

{| class="wikitable"
|-
! style="width:300pt;"| Family
! style="width:100pt;"| [[InterPro]]
! style="width:100pt;"| [[Pfam]]
! style="width:100pt;"| [[Structural Classification of Proteins|SCOP]]
|-
| [[basic helix-loop-helix]]<ref name="pmid7553065">{{Cite journal |vauthors=Littlewood TD, Evan GI |year=1995 |title=Transcription factors 2: helix-loop-helix |journal=Protein Profile |volume=2 |issue=6 |pages=621–702 |pmid=7553065}}</ref>
| {{InterPro|IPR001092}}
| {{Pfam|PF00010}}
| {{SCOP|47460}}
|-
| basic-leucine zipper ([[bZIP domain|bZIP]])<ref name="pmid12192032">{{Cite journal |vauthors=Vinson C, Myakishev M, Acharya A, Mir AA, Moll JR, Bonovich M |date=September 2002 |title=Classification of human B-ZIP proteins based on dimerization properties |journal=Molecular and Cellular Biology |volume=22 |issue=18 |pages=6321–35 |doi=10.1128/MCB.22.18.6321-6335.2002 |pmc=135624 |pmid=12192032}}</ref>
| {{InterPro|IPR004827}}
| {{Pfam|PF00170}}
| {{SCOP|57959}}
|-
| C-terminal effector domain of the bipartite response regulators
| {{InterPro|IPR001789}}
| {{Pfam|PF00072}}
| {{SCOP|46894}}
|-
| AP2/ERF/GCC box
| {{InterPro|IPR001471}}
| {{Pfam|PF00847}}
| {{SCOP|54176}}
|-
| [[helix-turn-helix]]<ref name="pmid8831795">{{Cite journal |vauthors=Wintjens R, Rooman M |date=September 1996 |title=Structural classification of HTH DNA-binding domains and protein-DNA interaction modes |journal=Journal of Molecular Biology |volume=262 |issue=2 |pages=294–313 |doi=10.1006/jmbi.1996.0514 |pmid=8831795}}</ref>
|
|
|
|-
| [[homeodomain fold|homeodomain proteins]], which are encoded by [[homeobox]] genes, are transcription factors.  Homeodomain proteins play critical roles in the regulation of [[developmental biology|development]].<ref name="pmid7979246">{{Cite journal |vauthors=Gehring WJ, Affolter M, Bürglin T |year=1994 |title=Homeodomain proteins |journal=Annual Review of Biochemistry |volume=63 |pages=487–526 |doi=10.1146/annurev.bi.63.070194.002415 |pmid=7979246}}</ref><ref name="pmid 26464018">{{Cite journal |vauthors=Bürglin TR, Affolter M |date=June 2016 |title=Homeodomain proteins: an update |journal=Chromosoma |volume=125 |issue=3 |pages=497–521 |doi=10.1007/s00412-015-0543-8 |pmc=4901127 |pmid=26464018}}</ref>
| {{InterPro|IPR009057}}
| {{Pfam|PF00046}}
| {{SCOP|46689}}
|-
| [[CI protein|lambda repressor]]-like
| {{InterPro|IPR010982}}
|
| {{SCOP|47413}}
|-
| srf-like ([[serum response factor]])
| {{InterPro|IPR002100}}
| {{Pfam|PF00319}}
| {{SCOP|55455}}
|-
| [[pax genes|paired box]]<ref name="pmid9297966">{{Cite journal |vauthors=Dahl E, Koseki H, Balling R |date=September 1997 |title=Pax genes and organogenesis |journal=BioEssays |volume=19 |issue=9 |pages=755–65 |doi=10.1002/bies.950190905 |pmid=9297966 |s2cid=23755557}}</ref>
|
|
|
|-
| [[winged helix]]
| {{InterPro|IPR013196}}
| {{Pfam|PF08279}}
| {{SCOP|46785}}
|-
| [[zinc finger]]s<ref name="pmid11179890">{{Cite journal |vauthors=Laity JH, Lee BM, Wright PE |date=February 2001 |title=Zinc finger proteins: new insights into structural and functional diversity |journal=Current Opinion in Structural Biology |volume=11 |issue=1 |pages=39–46 |doi=10.1016/S0959-440X(00)00167-6 |pmid=11179890}}</ref>
|
|
|
|-
| * multi-domain Cys<sub>2</sub>His<sub>2</sub> zinc fingers<ref name="pmid10940247">{{Cite journal |vauthors=Wolfe SA, Nekludova L, Pabo CO |year=2000 |title=DNA recognition by Cys2His2 zinc finger proteins |journal=Annual Review of Biophysics and Biomolecular Structure |volume=29 |pages=183–212 |doi=10.1146/annurev.biophys.29.1.183 |pmid=10940247}}</ref>
| {{InterPro|IPR007087}}
| {{Pfam|PF00096}}
| {{SCOP|57667}}
|-
| * Zn<sub>2</sub>/Cys<sub>6</sub>
|
|
| {{SCOP|57701}}
|-
| * Zn<sub>2</sub>/Cys<sub>8</sub> [[nuclear receptor]] zinc finger
| {{InterPro|IPR001628}}
| {{Pfam|PF00105}}
| {{SCOP|57716}}
|}

=== Response elements ===

The DNA sequence that a transcription factor binds to is called a [[transcription factor-binding site]] or [[response element]].<ref name="pmid15711128">{{Cite journal |vauthors=Wang JC |date=March 2005 |title=Finding primary targets of transcriptional regulators |url=http://www.landesbioscience.com/journals/cc/abstract.php?id=1521 |journal=Cell Cycle |volume=4 |issue=3 |pages=356–8 |doi=10.4161/cc.4.3.1521 |pmid=15711128 |doi-access=free}}</ref>

Transcription factors interact with their binding sites using a combination of [[Coulomb's law|electrostatic]] (of which [[hydrogen bond]]s are a special case) and [[Van der Waals force]]s.  Due to the nature of these chemical interactions, most transcription factors bind DNA in a sequence specific manner.  However, not all [[Base pair|bases]] in the transcription factor-binding site may actually interact with the transcription factor.  In addition, some of these interactions may be weaker than others.  Thus, transcription factors do not bind just one sequence but are capable of binding a subset of closely related sequences, each with a different strength of interaction.{{citation needed|date=March 2024}}

For example, although the [[consensus sequence|consensus binding site]] for the [[TATA-binding protein]] (TBP) is TATAAAA, the TBP transcription factor can also bind similar sequences such as TATATAT or TATATAA.<ref>{{Cite journal |last1=Savinkova |first1=Ludmila |last2=Drachkova |first2=Irina |last3=Arshinova |first3=Tatyana |last4=Ponomarenko |first4=Petr |last5=Ponomarenko |first5=Mikhail |last6=Kolchanov |first6=Nikolay |date=2013-02-12 |title=An Experimental Verification of the Predicted Effects of Promoter TATA-Box Polymorphisms Associated with Human Diseases on Interactions between the TATA Boxes and TATA-Binding Protein |journal=PLOS ONE |language=en |volume=8 |issue=2 |article-number=e54626 |doi=10.1371/journal.pone.0054626 |doi-access=free |issn=1932-6203 |pmc=3570547 |pmid=23424617 |bibcode=2013PLoSO...854626S }}</ref>

Because transcription factors can bind a set of related sequences and these sequences tend to be short, potential transcription factor binding sites can occur by chance if the DNA sequence is long enough.  It is unlikely, however, that a transcription factor will bind all compatible sequences in the [[genome]] of the [[cell (biology)|cell]].  Other constraints, such as DNA accessibility in the cell or availability of [[cofactor (biochemistry)|cofactors]] may also help dictate where a transcription factor will actually bind.  Thus, given the genome sequence, it is still difficult to predict where a transcription factor will actually bind in a living cell.

Additional recognition specificity, however, may be obtained through the use of more than one DNA-binding domain (for example tandem DBDs in the same transcription factor or through dimerization of two transcription factors) that bind to two or more adjacent sequences of DNA.

== Clinical significance ==
Transcription factors are of clinical significance for at least two reasons: (1) mutations can be associated with specific diseases, and (2) they can be targets of medications.

=== Disorders ===
Due to their important roles in development, intercellular signaling, and cell cycle, some human diseases have been associated with [[mutation]]s in transcription factors.<ref name="isbn0-19-511239-3">{{Cite book | vauthors = Semenza GL  |url= https://archive.org/details/transcriptionfac00seme |title=Transcription factors and human disease |publisher=Oxford University Press |year=1999 |isbn=978-0-19-511239-9 |location=Oxford [Oxfordshire] |url-access=registration}}</ref>

Many transcription factors are either [[tumor suppressor]]s or [[oncogene]]s, and, thus, mutations or aberrant regulation of them is associated with cancer. Three groups of transcription factors are known to be important in human cancer: (1) the [[NF-kappaB]] and [[AP-1 transcription factor|AP-1]] families, (2) the [[STAT protein|STAT]] family and (3) the [[steroid hormone receptor|steroid receptors]].<ref name="pmid16475943">{{Cite journal |vauthors=Libermann TA, Zerbini LF |date=February 2006 |title=Targeting transcription factors for cancer gene therapy |journal=Current Gene Therapy |volume=6 |issue=1 |pages=17–33 |doi=10.2174/156652306775515501 |pmid=16475943}}</ref>

Below are a few of the better-studied examples:

{| class="wikitable"
|-
! Condition
! Description
! Locus
|-
| [[Rett syndrome]]
| Mutations in the [[MECP2]] transcription factor are associated with [[Rett syndrome]], a neurodevelopmental disorder.<ref name="pmid16647848">{{Cite journal |vauthors=Moretti P, Zoghbi HY |date=June 2006 |title=MeCP2 dysfunction in Rett syndrome and related disorders |journal=Current Opinion in Genetics & Development |volume=16 |issue=3 |pages=276–81 |doi=10.1016/j.gde.2006.04.009 |pmid=16647848}}</ref><ref name="pmid17317146">{{Cite journal |vauthors=Chadwick LH, Wade PA |date=April 2007 |title=MeCP2 in Rett syndrome: transcriptional repressor or chromatin architectural protein? |url=https://zenodo.org/record/1258987 |url-status=live |journal=Current Opinion in Genetics & Development |volume=17 |issue=2 |pages=121–5 |doi=10.1016/j.gde.2007.02.003 |pmid=17317146 |archive-url=https://web.archive.org/web/20231002233545/https://zenodo.org/record/1258987 |archive-date=Oct 2, 2023 |via=Zenodo}}</ref>
| Xq28
|-
| [[Diabetes]]
| A rare form of [[diabetes]] called [[MODY]] (Maturity onset diabetes of the young) can be caused by mutations in [[hepatocyte nuclear factors]] (HNFs)<ref name="pmid17923767">{{Cite book |title=Distinct roles of HNF1beta, HNF1alpha, and HNF4alpha in regulating pancreas development, beta-cell function and growth |vauthors=Maestro MA, Cardalda C, Boj SF, Luco RF, Servitja JM, Ferrer J |publisher=Karger Medical and Scientific Publishers |year=2007 |isbn=978-3-8055-8385-5 |series=Endocrine Development |volume=12 |pages=33–45 |chapter=Distinct Roles of HNF1 Β, HNF1 α, and HNF4 α in Regulating Pancreas Development, Β -Cell Function and Growth |doi=10.1159/000109603 |pmid=17923767 |chapter-url=https://books.google.com/books?id=AzvFFxY-3CMC&pg=PA33}}</ref> or [[Pdx1|insulin promoter factor-1]] (IPF1/Pdx1).<ref name="pmid18360684">{{Cite journal |vauthors=Al-Quobaili F, Montenarh M |date=April 2008 |title=Pancreatic duodenal homeobox factor-1 and diabetes mellitus type 2 (review) |url=https://www.spandidos-publications.com/ijmm/article.jsp?article_id=ijmm_21_4_399 |url-status=live |journal=International Journal of Molecular Medicine |volume=21 |issue=4 |pages=399–404 |doi=10.3892/ijmm.21.4.399 |pmid=18360684 |archive-url=https://web.archive.org/web/20231002232026/https://www.spandidos-publications.com/ijmm/21/4/399/abstract |archive-date=Oct 2, 2023 |doi-access=free}}</ref>
| multiple
|-
| [[Apraxia of speech#Childhood apraxia of speech|Developmental verbal dyspraxia]]
| Mutations in the [[FOXP2]] transcription factor are associated with [[Apraxia of speech#Childhood apraxia of speech|developmental verbal dyspraxia]], a disease in which individuals are unable to produce the finely coordinated movements required for speech.<ref name="pmid17330859">{{Cite journal |vauthors=Lennon PA, Cooper ML, Peiffer DA, Gunderson KL, Patel A, Peters S, Cheung SW, Bacino CA |date=April 2007 |title=Deletion of 7q31.1 supports involvement of ''FOXP2'' in language impairment: clinical report and review |journal=American Journal of Medical Genetics. Part A |volume=143A |issue=8 |pages=791–8 |doi=10.1002/ajmg.a.31632 |pmid=17330859 |s2cid=22021740}}</ref>
| 7q31
|-
| [[Autoimmune diseases]]
| Mutations in the [[FOXP3]] transcription factor cause a rare form of [[autoimmune disease]] called [[IPEX (syndrome)|IPEX]].<ref name="pmid18317533">{{Cite journal |vauthors=van der Vliet HJ, Nieuwenhuis EE |year=2007 |title=IPEX as a result of mutations in FOXP3 |journal=Clinical & Developmental Immunology |volume=2007 |pages=1–5 |doi=10.1155/2007/89017 |pmc=2248278 |pmid=18317533 |doi-access=free}}</ref>
| Xp11.23-q13.3
|-
| [[Li-Fraumeni syndrome]]
| Caused by mutations in the tumor suppressor [[p53 (protein)|p53]].<ref name="pmid15917654">{{Cite journal |vauthors=Iwakuma T, Lozano G, Flores ER |date=July 2005 |title=Li-Fraumeni syndrome: a p53 family affair |journal=Cell Cycle |volume=4 |issue=7 |pages=865–7 |doi=10.4161/cc.4.7.1800 |pmid=15917654 |doi-access=free}}</ref>
| 17p13.1
|-
| [[Breast cancer]]
| The [[STAT protein|STAT]] family is relevant to [[breast cancer]].<ref>{{Cite journal |vauthors=Clevenger CV |date=November 2004 |title=Roles and Regulation of Stat Family Transcription Factors in Human Breast Cancer |journal=American Journal of Pathology |type=Review |volume=165 |issue=5 |pages=1449–1460 |doi=10.1016/S0002-9440(10)63403-7 |pmc=1618660 |pmid=15509516 |doi-access=free}}</ref>
| multiple
|-
| Multiple cancers
| The [[HOX gene|HOX]] family are involved in a variety of cancers.<ref>{{Cite web |title="Transcription factors as targets and markers in cancer" Workshop 2007 |url=http://www.ias.surrey.ac.uk/reports/hox-report.html |archive-url=https://web.archive.org/web/20120525104734/http://www.ias.surrey.ac.uk/reports/hox-report.html |archive-date=25 May 2012 |access-date=14 December 2009}}</ref>
| multiple
|-
|[[Osteoarthritis]]
|[[Mutation]] or reduced activity of [[SOX9]]<ref>{{Cite journal |vauthors=Govindaraj K, Hendriks J, Lidke DS, Karperien M, Post JN |date=January 2019 |title=Changes in Fluorescence Recovery After Photobleaching (FRAP) as an indicator of SOX9 transcription factor activity |journal=Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms |volume=1862 |issue=1 |pages=107–117 |doi=10.1016/j.bbagrm.2018.11.001 |pmid=30465885 |doi-access=free}}</ref>
|
|}

=== Potential drug targets ===
{{See also|Therapeutic gene modulation}}

Approximately 10% of currently prescribed drugs directly target the [[nuclear receptor]] class of transcription factors.<ref name="pmid17139284">{{Cite journal |vauthors=Overington JP, Al-Lazikani B, Hopkins AL |date=December 2006 |title=How many drug targets are there? |journal=Nature Reviews. Drug Discovery |volume=5 |issue=12 |pages=993–6 |doi=10.1038/nrd2199 |pmid=17139284 |s2cid=11979420}}</ref> Examples include [[tamoxifen]] and [[bicalutamide]] for the treatment of [[breast cancer|breast]] and [[prostate cancer]], respectively, and various types of [[Glucocorticoid#Anti-inflammatory|anti-inflammatory]] and [[anabolic steroid|anabolic]] [[steroid]]s.<ref>{{Cite journal |vauthors=Gronemeyer H, Gustafsson JA, Laudet V |date=November 2004 |title=Principles for modulation of the nuclear receptor superfamily |journal=Nature Reviews. Drug Discovery |volume=3 |issue=11 |pages=950–64 |doi=10.1038/nrd1551 |pmid=15520817 |s2cid=205475111}}</ref> In addition, transcription factors are often indirectly modulated by drugs through [[signaling cascade]]s. It might be possible to directly target other less-explored transcription factors such as [[NF-κB#As a drug target|NF-κB]] with drugs.<ref name="pmid8049612">{{Cite journal |vauthors=Bustin SA, McKay IA |date=June 1994 |title=Transcription factors: targets for new designer drugs |journal=British Journal of Biomedical Science |volume=51 |issue=2 |pages=147–57 |pmid=8049612}}</ref><ref name="pmid7549464">{{Cite journal |vauthors=Butt TR, Karathanasis SK |year=1995 |title=Transcription factors as drug targets: opportunities for therapeutic selectivity |journal=Gene Expression |volume=4 |issue=6 |pages=319–36 |pmc=6134363 |pmid=7549464}}</ref><ref name="pmid9755455">{{Cite journal |vauthors=Papavassiliou AG |date=August 1998 |title=Transcription-factor-modulating agents: precision and selectivity in drug design |journal=Molecular Medicine Today |volume=4 |issue=8 |pages=358–66 |doi=10.1016/S1357-4310(98)01303-3 |pmid=9755455}}</ref><ref name="pmid15790306">{{Cite journal |vauthors=Ghosh D, Papavassiliou AG |year=2005 |title=Transcription factor therapeutics: long-shot or lodestone |journal=Current Medicinal Chemistry |volume=12 |issue=6 |pages=691–701 |doi=10.2174/0929867053202197 |pmid=15790306}}</ref> Transcription factors outside the nuclear receptor family are thought to be more difficult to target with [[small molecule]] therapeutics since it is not clear that they are [[drug design#Rational drug discovery|"drugable"]] but progress has been made on Pax2<ref name="pmid28094913">{{Cite journal |vauthors=Grimley E, Liao C, Ranghini E, Nikolovska-Coleska Z, Dressler G |year=2017 |title=Inhibition of Pax2 Transcription Activation with a Small Molecule that Targets the DNA Binding Domain |journal=ACS Chemical Biology |volume=12 |issue=3 |pages=724–734 |doi=10.1021/acschembio.6b00782 |pmc=5761330 |pmid=28094913}}</ref><ref name="pmid29685496">{{Cite journal |vauthors=Grimley E, Dressler GR |year=2018 |title=Are Pax proteins potential therapeutic targets in kidney disease and cancer? |journal=Kidney International |volume=94 |issue=2 |pages=259–267 |doi=10.1016/j.kint.2018.01.025 |pmc=6054895 |pmid=29685496}}</ref> and the [[notch signaling pathway|notch]] pathway.<ref name="pmid19907488">{{Cite journal |vauthors=Moellering RE, Cornejo M, Davis TN, Del Bianco C, Aster JC, Blacklow SC, Kung AL, Gilliland DG, Verdine GL, Bradner JE |date=November 2009 |title=Direct inhibition of the NOTCH transcription factor complex |journal=Nature |volume=462 |issue=7270 |pages=182–8 |bibcode=2009Natur.462..182M |doi=10.1038/nature08543 |pmc=2951323 |pmid=19907488}}
* {{lay source |template=cite magazine |author=Katherine Bagley |date=11 November 2009 |title=New drug target for cancer |url=http://www.the-scientist.com/blog/display/56143/ |archive-url=https://web.archive.org/web/20091116103443/http://www.the-scientist.com/blog/display/56143/ |archive-date=16 November 2009 |magazine=The Scientist}}</ref>

== Role in evolution ==
{{Further|Evolutionary developmental biology}}

Gene duplications have played a crucial role in the [[evolution]] of species. This applies particularly to transcription factors. Once they occur as duplicates, accumulated mutations encoding for one copy can take place without negatively affecting the regulation of downstream targets. However, changes of the DNA binding specificities of the single-copy [[Leafy]] transcription factor, which occurs in most land plants, have recently been elucidated. In that respect, a single-copy transcription factor can undergo a change of specificity through a promiscuous intermediate without losing function. Similar mechanisms have been proposed in the context of all alternative [[phylogenetic]] hypotheses, and the role of transcription factors in the evolution of all species.<ref name="pmid24436181">{{Cite journal |vauthors=Sayou C, Monniaux M, Nanao MH, Moyroud E, Brockington SF, Thévenon E, Chahtane H, Warthmann N, Melkonian M, Zhang Y, Wong GK, Weigel D, Parcy F, Dumas R |date=February 2014 |title=A promiscuous intermediate underlies the evolution of LEAFY DNA binding specificity |url=https://zenodo.org/record/3437650 |journal=Science |volume=343 |issue=6171 |pages=645–8 |bibcode=2014Sci...343..645S |doi=10.1126/science.1248229 |pmid=24436181 |s2cid=207778924 |hdl-access=free |hdl=1885/64773}}{{Dead link|date=July 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref name="MBE_1767">{{Cite journal |vauthors=Jin J, He K, Tang X, Li Z, Lv L, Zhao Y, Luo J, Gao G |date=July 2015 |title=An Arabidopsis Transcriptional Regulatory Map Reveals Distinct Functional and Evolutionary Features of Novel Transcription Factors |journal=Molecular Biology and Evolution |volume=32 |issue=7 |pages=1767–73 |doi=10.1093/molbev/msv058 |pmc=4476157 |pmid=25750178}}</ref>

== Role in biocontrol activity ==
The transcription factors have a role in [[Resistance (ecology)|resistance]] activity which is important for successful [[biocontrol]] activity. The resistant to [[oxidative stress]] and alkaline pH sensing were contributed from the transcription factor Yap1 and Rim101 of the ''[[Papiliotrema|Papiliotrema terrestris]]'' LS28 as molecular tools revealed an understanding of the genetic mechanisms underlying the biocontrol activity which supports [[Disease management (agriculture)|disease management]] programs based on biological and integrated control.<ref>{{Cite journal |vauthors=Castoria R, Miccoli C, Barone G, Palmieri D, De Curtis F, Lima G, Heitman J, Ianiri G |date=March 2021 |title=Molecular Tools for the Yeast Papiliotrema terrestris LS28 and Identification of Yap1 as a Transcription Factor Involved in Biocontrol Activity |journal=Applied and Environmental Microbiology |volume=87 |issue=7 |bibcode=2021ApEnM..87E2910C |doi=10.1128/AEM.02910-20 |pmc=8091616 |pmid=33452020 |veditors=Cann I |article-number=e02910-20 }}</ref>

== Analysis ==

There are different technologies available to analyze transcription factors. On the [[genomic]] level, DNA-[[sequencing]] and database research are commonly used.<ref name="pmid16845064">{{Cite journal |vauthors=Grau J, Ben-Gal I, Posch S, Grosse I |date=July 2006 |title=VOMBAT: prediction of transcription factor binding sites using variable order Bayesian trees |url=http://www.eng.tau.ac.il/~bengal/VOMBAT.pdf |journal=Nucleic Acids Research |volume=34 |issue=Web Server issue |pages=W529-33 |doi=10.1093/nar/gkl212 |pmc=1538886 |pmid=16845064 |archive-url=https://web.archive.org/web/20180930084306/http://www.eng.tau.ac.il/~bengal/VOMBAT.pdf |archive-date=30 September 2018 |access-date=10 January 2014}}</ref> The protein version of the transcription factor is detectable by using specific [[antibodies]]. The sample is detected on a [[western blot]]. By using [[electrophoretic mobility shift assay]] (EMSA),<ref name="pmid:18591661">{{Cite journal |vauthors=Wenta N, Strauss H, Meyer S, Vinkemeier U |date=July 2008 |title=Tyrosine phosphorylation regulates the partitioning of STAT1 between different dimer conformations |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=105 |issue=27 |pages=9238–43 |bibcode=2008PNAS..105.9238W |doi=10.1073/pnas.0802130105 |pmc=2453697 |pmid=18591661 |doi-access=free}}</ref> the activation profile of transcription factors can be detected. A [[multiplex (assay)|multiplex]] approach for activation profiling is a TF chip system where several different transcription factors can be detected in parallel.<ref>{{Cite journal |last1=Trauernicht |first1=Max |last2=Filipovska |first2=Teodora |last3=Rastogi |first3=Chaitanya |last4=Steensel |first4=Bas van |date=2024-12-18 |title=Optimized reporters for multiplexed detection of transcription factor activity |journal=Cell Systems |language=English |volume=15 |issue=12 |pages=1107–1122.e7 |doi=10.1016/j.cels.2024.11.003 |issn=2405-4712 |pmc=11667439 |pmid=39644900}}</ref>

The most commonly used method for identifying transcription factor binding sites is [[chromatin immunoprecipitation]] (ChIP).<ref>{{Cite journal |vauthors=Furey TS |date=December 2012 |title=ChIP-seq and beyond: new and improved methodologies to detect and characterize protein-DNA interactions |journal=Nature Reviews. Genetics |volume=13 |issue=12 |pages=840–52 |doi=10.1038/nrg3306 |pmc=3591838 |pmid=23090257}}</ref> This technique relies on chemical fixation of chromatin with [[formaldehyde]], followed by co-precipitation of DNA and the transcription factor of interest using an [[antibody]] that specifically targets that protein. The DNA sequences can then be identified by microarray or high-throughput sequencing ([[ChIP-sequencing|ChIP-seq]]) to determine transcription factor binding sites. If no antibody is available for the protein of interest, [[DNA adenine methyltransferase identification|DamID]] may be a convenient alternative.<ref>{{Cite journal |vauthors=Aughey GN, Southall TD |date=January 2016 |title=Dam it's good! DamID profiling of protein-DNA interactions |journal=Wiley Interdisciplinary Reviews: Developmental Biology |volume=5 |issue=1 |pages=25–37 |doi=10.1002/wdev.205 |pmc=4737221 |pmid=26383089}}</ref>

== Classes ==

As described in more detail below, transcription factors may be classified by their (1) mechanism of action, (2) regulatory function, or (3) sequence homology (and hence structural similarity) in their DNA-binding domains. They are also classified by 3D structure of their DBD and the way it contacts DNA.<ref name=":0">{{cite journal | vauthors = Wingender E, Schoeps T, Haubrock M, Dönitz J | title = TFClass: a classification of human transcription factors and their rodent orthologs | journal = Nucleic Acids Research | volume = 43 | issue = Database issue | pages = D97-102 | date = January 2015 | pmid = 25361979 | pmc = 4383905 | doi = 10.1093/nar/gku1064 }}</ref><ref name=":1">{{cite journal | vauthors = Blanc-Mathieu R, Dumas R, Turchi L, Lucas J, Parcy F | title = Plant-TFClass: a structural classification for plant transcription factors | journal = Trends in Plant Science | volume = 29 | issue = 1 | pages = 40–51 | date = January 2024 | pmid = 37482504 | doi = 10.1016/j.tplants.2023.06.023 | bibcode = 2024TPS....29...40B | url = https://hal.science/hal-04212079 }}</ref>

=== Mechanistic ===

There are two mechanistic classes of transcription factors:
* [[General transcription factor]]s are involved in the formation of a [[Transcription preinitiation complex|preinitiation complex]]. The most common are abbreviated as [[TFIIA]], [[TFIIB]], [[TFIID]], [[TFIIE]], [[TFIIF]], and [[TFIIH]]. They are ubiquitous and interact with the core promoter region surrounding the transcription start site(s) of all [[class II gene]]s.<ref name="pmidc">{{Cite journal |vauthors=Orphanides G, Lagrange T, Reinberg D |date=November 1996 |title=The general transcription factors of RNA polymerase II |journal=Genes & Development |volume=10 |issue=21 |pages=2657–83 |doi=10.1101/gad.10.21.2657 |pmid=8946909 |doi-access=free}}</ref>
* '''Upstream transcription factors''' are proteins that bind somewhere upstream of the initiation site to stimulate or repress transcription. These are roughly synonymous with '''specific transcription factors''', because they vary considerably depending on what [[recognition sequence]]s are present in the proximity of the gene.<ref name="boron125-126">{{Cite book |title=Medical Physiology: A Cellular And Molecular Approaoch |vauthors=Boron WF |publisher=Elsevier/Saunders |year=2003 |isbn=1-4160-2328-3 |pages=125–126}}</ref>

{|class="wikitable"
!colspan=4| Examples of specific transcription factors<ref name="boron125-126" />
|-
! Factor !! Structural type !! [[Recognition sequence]] !! Binds as
|-
! [[Sp1 transcription factor|SP1]]
| [[Zinc finger]] || [[five prime end|5']]-GGGCGG-[[three prime end|3']] || Monomer
|-
! [[AP-1 transcription factor|AP-1]]
| [[Basic zipper]] || 5'-TGA(G/C)TCA-3' || Dimer
|-
! [[Ccaat-enhancer-binding proteins|C/EBP]]
| [[Basic zipper]] || 5'-ATTGCGCAAT-3' || Dimer
|-
! [[Heat shock factor]]
| [[Basic zipper]] || 5'-XGAAX-3' || Trimer
|-
! [[ATF/CREB]]
| [[Basic zipper]] || 5'-TGACGTCA-3' || Dimer
|-
! [[Myc|c-Myc]]
| [[Basic helix-loop-helix]]
| 5'-CACGTG-3' || Dimer
|-
! [[POU2F1|Oct-1]]
| [[Helix-turn-helix]] || 5'-ATGCAAAT-3' || Monomer
|-
! [[Nuclear factor 1|NF-1]]
| Novel || 5'-TTGGCXXXXXGCCAA-3' || Dimer
|-
|colspan=4| (G/C) = G or C <br /> X = [[adenine|A]], [[thymine|T]], [[guanine|G]] or [[cytosine|C]]
|}

=== Functional ===

Transcription factors have been classified according to their regulatory function:<ref name="pmid11823631" />
* I. '''Constitutive''' – present in all cells at all times, constantly active, all being [[Activator (genetics)|activators]]. Very likely playing an important facilitating role in the transcription of many chromosomal genes, possibly in genes that seem to be always transcribed (e.g., structural proteins like tubulin and actin, and ubiquitous metabolic enzymes such as glyceraldehyde phosphate dehydrogenase (GAPDH)). E.g.: [[general transcription factor]]s, [[Sp1 transcription factor|Sp1]], [[Nuclear factor 1|NF1]], [[Ccaat-enhancer-binding proteins|CCAAT]]
* II. '''Regulatory (conditionally active)''' – require activation.
** II.A '''Developmental''' '''(cell-type specific)''' – beginning in a fertilized egg. Once expressed, require no additional activation. E.g.:[[GATA transcription factor|GATA]], [[hepatocyte nuclear factors|HNF]], [[PIT-1]], [[MyoD]], [[Myf5]], [[Hox (gene)|Hox]], [[winged-helix transcription factors|Winged Helix]]
** II.B '''Signal-dependent''' – may be either developmentally restricted in their expression or present in most or all cells, but all are inactive (or minimally active) until cells containing such proteins are exposed to the appropriate intra- or extracellular signal.
*** II.B.1 '''Extracellular ligand ([[endocrine system|endocrine]] or [[paracrine signalling|paracrine]])-dependent''' – [[nuclear receptor]]s.
*** II.B.2 '''Intracellular ligand ([[autocrine signalling|autocrine]])-dependent''' – activated by small intracellular molecules. E.g.: [[Sterol regulatory element binding protein|SREBP]], [[p53]], orphan nuclear receptors.
*** II.B.3 '''Cell surface receptor-ligand interaction-dependent''' – activated by second messenger signaling cascades.
**** II.B.3.a Constitutive nuclear factors activated by serine phosphorylation – residing within the nucleus. The serine phosphorylation enzymes can be activated by two main routes:
***** [[G protein-coupled receptor]]s upon ligand binding increase intracellular levels of [[Second messenger system|second messengers]] ([[Cyclic adenosine monophosphate|cAMP]], [[Inositol trisphosphate|IP<sub>3</sub>]], [[Diglyceride|DAG]], calcium) which, in turn, activate protein [[serine-threonine kinase]] enzymes (such as [[Protein kinase A|PKA]], [[Protein kinase C|PKC]]).
***** [[Receptor tyrosine kinase]]s upon ligand binding trigger other pathways that finally terminate in serine phosphorylation of the abundant resident nuclear transcription factors.
***** Examples include: [[CREB]], [[AP-1 (transcription factor)|AP-1]], [[Mef2]]
**** II.B.3.b '''Latent cytoplasmic factors''' – residing in the cytoplasm when inactive. Structurally and chemically very diverse group, and so are their activation pathways. E.g.: [[STAT protein|STAT]], [[R-SMAD]], [[NF-κB]], [[Notch signaling|Notch]], [[Tubby protein|TUBBY]], [[NFAT]]

=== Structural ===

Transcription factors are often classified based on the [[Sequence homology#Homology of sequences in genetics|sequence similarity]] and hence the [[tertiary structure]] of their DNA-binding domains.<ref name="pmid15706513">{{Cite journal |vauthors=Stegmaier P, Kel AE, Wingender E |year=2004 |title=Systematic DNA-binding domain classification of transcription factors |url=http://www.jsbi.org/journal/GIW04/GIW04F028.html |journal=Genome Informatics. International Conference on Genome Informatics |volume=15 |issue=2 |pages=276–86 |pmid=15706513 |archive-url=https://web.archive.org/web/20130619202726/http://www.jsbi.org/journal/GIW04/GIW04F028.html |archive-date=19 June 2013}}</ref><ref name="Matys_2006">{{Cite journal |vauthors=Matys V, Kel-Margoulis OV, Fricke E, Liebich I, Land S, Barre-Dirrie A, Reuter I, Chekmenev D, Krull M, Hornischer K, Voss N, Stegmaier P, Lewicki-Potapov B, Saxel H, Kel AE, Wingender E |date=January 2006 |title=TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes |journal=Nucleic Acids Research |volume=34 |issue=Database issue |pages=D108-10 |doi=10.1093/nar/gkj143 |pmc=1347505 |pmid=16381825}}</ref><ref>{{Cite web |title=TRANSFAC database |url=https://www.gene-regulation.com/pub/databases/transfac/cl.html |access-date=5 August 2007}}</ref><ref name="Jin_2014" /> The following classification is based on the 3D structure of their [[DNA-binding domain|DBD]] and the way it contacts DNA. It was first developed for Human TF and later extended to rodents <ref name=":0" /> and also to plants.<ref name=":1" /> 
* 1 Superclass: Basic Domains
** 1.1 Class: [[Leucine zipper]] factors ([[bZIP]])
*** 1.1.1 Family: [[AP-1 (transcription factor)|AP-1]](-like) components; includes ([[c-Fos]]/[[c-Jun]])
*** 1.1.2 Family: [[CREB]]
*** 1.1.3 Family: [[Ccaat-enhancer-binding proteins|C/EBP]]-like factors
*** 1.1.4 Family: bZIP / [[PAR (transcription factor)|PAR]]
*** 1.1.5 Family: Plant G-box binding factors
*** 1.1.6 Family: ZIP only
** 1.2 Class: Helix-loop-helix factors ([[bHLH]])
*** 1.2.1 Family: Ubiquitous (class A) factors
*** 1.2.2 Family: Myogenic transcription factors ([[MyoD]])
*** 1.2.3 Family: Achaete-Scute
*** 1.2.4 Family: Tal/Twist/Atonal/Hen
** 1.3 Class: Helix-loop-helix / leucine zipper factors ([[basic helix-loop-helix leucine zipper transcription factors|bHLH-ZIP]])
*** 1.3.1 Family: Ubiquitous bHLH-ZIP factors; includes USF  ([[USF1]], [[USF2]]); SREBP ([[Sterol regulatory element binding protein|SREBP]])
*** 1.3.2 Family: Cell-cycle controlling factors; includes [[Myc|c-Myc]]
** 1.4 Class: NF-1
*** 1.4.1 Family: NF-1  ([[NFIA|A]], [[NFIB (gene)|B]], [[NFIC (gene)|C]], [[NFIX|X]])
** 1.5 Class: RF-X
*** 1.5.1 Family: RF-X ([[RFX1|1]], [[RFX2|2]], [[RFX3|3]], [[RFX4|4]], [[RFX5|5]], [[RFXANK|ANK]])
** 1.6 Class: bHSH
* 2 Superclass: Zinc-coordinating DNA-binding domains
** 2.1 Class: Cys4 [[zinc finger]] of [[nuclear receptor]] type
*** 2.1.1 Family: [[Steroid hormone receptor]]s
*** 2.1.2 Family: [[Thyroid hormone receptor]]-like factors
** 2.2 Class: diverse Cys4 zinc fingers
*** 2.2.1 Family: [[GATA transcription factor|GATA-Factors]]
** 2.3 Class: Cys2His2 zinc finger domain
*** 2.3.1 Family: Ubiquitous factors, includes [[TFIIIA]], [[Sp1 transcription factor|Sp1]]
*** 2.3.2 Family: Developmental / cell cycle regulators; includes [[Krüppel]]
*** 2.3.4 Family: Large factors with NF-6B-like binding properties
** 2.4 Class: Cys6 cysteine-zinc cluster
** 2.5 Class: Zinc fingers of alternating composition
* 3 Superclass: [[Helix-turn-helix]]
** 3.1 Class: [[Homeobox|Homeo domain]]
*** 3.1.1 Family: Homeo domain only; includes [[Ubx]]
*** 3.1.2 Family: [[POU family|POU domain]] factors; includes [[Octamer transcription factor|Oct]]
*** 3.1.3 Family: Homeo domain with LIM region
*** 3.1.4 Family: homeo domain plus zinc finger motifs
** 3.2 Class: Paired box
*** 3.2.1 Family: Paired plus homeo domain
*** 3.2.2 Family: Paired domain only
** 3.3 Class: [[FOX proteins|Fork head]] / [[Winged-helix transcription factors|winged helix]]
*** 3.3.1 Family: Developmental regulators; includes [[forkhead]]
*** 3.3.2 Family: Tissue-specific regulators
*** 3.3.3 Family: Cell-cycle controlling factors
*** 3.3.0 Family: Other regulators
** 3.4 Class: [[Heat Shock Factor]]s
*** 3.4.1 Family: HSF
** 3.5 Class: Tryptophan clusters
*** 3.5.1 Family: Myb
*** 3.5.2 Family: Ets-type
*** 3.5.3 Family: [[Interferon regulatory factors]]
** 3.6 Class: TEA (transcriptional enhancer factor) domain
*** 3.6.1 Family: TEA ([[TEAD1]], [[TEAD2]], [[TEAD3]], [[TEAD4]])
* 4 Superclass: beta-Scaffold Factors with Minor Groove Contacts
** 4.1 Class: RHR ([[Rel homology domain|Rel homology region]])
*** 4.1.1 Family: Rel/[[Ankyrin repeat|ankyrin]]; [[NF-κB|NF-kappaB]]
*** 4.1.2 Family: ankyrin only
*** 4.1.3 Family: [[NFAT]] ('''N'''uclear '''F'''actor of '''A'''ctivated '''T'''-cells) ([[NFATC1]], [[NFATC2]], [[NFATC3]])
** 4.2 Class: STAT
*** 4.2.1 Family: [[STAT protein|STAT]]
** 4.3 Class: p53
*** 4.3.1 Family: [[p53]]
** 4.4 Class: [[MADS-box|MADS box]]
*** 4.4.1 Family: Regulators of differentiation; includes ([[Mef2]])
*** 4.4.2 Family: Responders to external signals, SRF ([[serum response factor]])  ({{gene|SRF}})
*** 4.4.3 Family: Metabolic regulators (ARG80)
** 4.5 Class: beta-Barrel alpha-helix transcription factors
** 4.6 Class: [[TATA binding protein]]s
*** 4.6.1 Family: TBP
** 4.7 Class: [[HMG-box]]
*** 4.7.1 Family: [[SOX genes]], [[SRY]]
*** 4.7.2 Family: TCF-1 ([[HNF1A|TCF1]])
*** 4.7.3 Family: HMG2-related, [[Structure specific recognition protein 1|SSRP1]]
*** 4.7.4 Family: UBF
*** 4.7.5 Family: MATA
** 4.8 Class: Heteromeric CCAAT factors
*** 4.8.1 Family: Heteromeric CCAAT factors
** 4.9 Class: Grainyhead
*** 4.9.1 Family: Grainyhead
** 4.10 Class: [[Cold-shock domain]] factors
*** 4.10.1 Family: csd
** 4.11 Class: Runt
*** 4.11.1 Family: Runt
* 0 Superclass: Other Transcription Factors
** 0.1 Class: Copper fist proteins
** 0.2 Class: HMGI(Y) ([[HMGA1]])
*** 0.2.1 Family: HMGI(Y)
** 0.3 Class: Pocket domain
** 0.4 Class: E1A-like factors
** 0.5 Class: AP2/EREBP-related factors
*** 0.5.1 Family: [[Apetala 2|AP2]]
*** 0.5.2 Family: EREBP
*** 0.5.3 Superfamily: [[B3 DNA-binding domain|AP2/B3]]
**** 0.5.3.1 Family: ARF
**** 0.5.3.2 Family: ABI
**** 0.5.3.3 Family: RAV

== Transcription factor databases ==
There are numerous databases cataloging information about transcription factors, but their scope and utility vary dramatically. Some may contain only information about the actual proteins, some about their binding sites, or about their target genes. Examples include the following:
* footprintDB - a metadatabase of multiple databases, including JASPAR and others
* [[JASPAR]]: database of transcription factor binding sites for eukaryotes
* PlantTFD: Plant transcription factor database<ref>{{Cite journal |vauthors=Jin J, Tian F, Yang DC, Meng YQ, Kong L, Luo J, Gao G |date=January 2017 |title=PlantTFDB 4.0: toward a central hub for transcription factors and regulatory interactions in plants |journal=Nucleic Acids Research |volume=45 |issue=D1 |pages=D1040–D1045 |doi=10.1093/nar/gkw982 |pmc=5210657 |pmid=27924042}}</ref>
* [[TcoF-DB]]: Database of transcription co-factors and transcription factor interactions<ref>{{Cite journal |vauthors=Schmeier S, Alam T, Essack M, Bajic VB |date=January 2017 |title=TcoF-DB v2: update of the database of human and mouse transcription co-factors and transcription factor interactions |journal=Nucleic Acids Research |volume=45 |issue=D1 |pages=D145–D150 |doi=10.1093/nar/gkw1007 |pmc=5210517 |pmid=27789689}}</ref>
* TFcheckpoint: database of human, mouse and rat TF candidates
* transcriptionfactor.org (now commercial, selling reagents)
* MethMotif.org: An integrative cell-specific database of transcription factor binding motifs coupled with DNA methylation profiles.<ref>{{Cite journal |author-link6=Touati Benoukraf |vauthors=Xuan Lin QX, Sian S, An O, Thieffry D, Jha S, Benoukraf T |date=January 2019 |title=MethMotif: an integrative cell specific database of transcription factor binding motifs coupled with DNA methylation profiles |journal=Nucleic Acids Research |volume=47 |issue=D1 |pages=D145–D154 |doi=10.1093/nar/gky1005 |pmc=6323897 |pmid=30380113}}</ref>

== See also ==
{{Div col|colwidth=30em}}
* [[Cdx protein family]]
* [[DNA-binding protein]]
* [[Inhibitor of DNA-binding protein]]
* [[Mapper(2)]]
* [[Nuclear receptor]], a class of ligand activated transcription factors
* [[Open Regulatory Annotation Database]]
* [[Phylogenetic footprinting]]
* [[TRANSFAC|TRANSFAC database]]
* [[YeTFaSCo]]
{{Div col end}}

== References ==
{{Reflist|33em}}

== Further reading ==
{{Refbegin}}
* Carretero-Paulet, Lorenzo;&nbsp;Galstyan, Anahit;&nbsp;Roig-Villanova, Irma;&nbsp;Martínez-García, Jaime F.;&nbsp;Bilbao-Castro, Jose R.&nbsp;«Genome-Wide Classification and Evolutionary Analysis of the bHLH Family of Transcription Factors in Arabidopsis, Poplar, Rice, Moss, and Algae».&nbsp;''Plant Physiology'',&nbsp;153,&nbsp;3,&nbsp;2010-07,&nbsp;pàg.&nbsp;1398–1412. [[doi:10.1104/pp.110.153593]]. {{ISSN|0032-0889}}
* {{Cite journal |vauthors=Jin J, He K, Tang X, Li Z, Lv L, Zhao Y, Luo J, Gao G |year=2015 |title=An Arabidopsis Transcriptional Regulatory Map Reveals Distinct Functional and Evolutionary Features of Novel Transcription Factors |journal=Molecular Biology and Evolution |volume=32 |issue=7 |pages=1767–73 |doi=10.1093/molbev/msv058 |pmc=4476157 |pmid=25750178}}
{{Refend}}

== External links ==
* {{MeshName|Transcription+Factors}}
* [https://transcriptionfactor.org/ Transcription factor database] {{Webarchive|url=https://web.archive.org/web/20081204232625/http://www.transcriptionfactor.org/ |date=4 December 2008 }}

{{Cell signaling}}
{{Transcription factors}}
{{Genarch}}
{{Authority control}}

[[Category:Gene expression]]
[[Category:Protein families]]
[[Category:Transcription factors| ]]
[[Category:DNA]]
[[Category:Biophysics]]
[[Category:Evolutionary developmental biology]]