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transcription factor
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{{short description|Protein that controls the rate of DNA transcription}}{{Use dmy dates|date=March 2014}}{{bots|deny=Citation bot}}{{Transcription factor glossary}}(File:Transcription Factors.svg|thumb|442px|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 of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence.JOURNAL, Latchman DS, Transcription factors: an overview, The International Journal of Biochemistry & Cell Biology, 29, 12, 1305–12, December 1997, 9570129, 10.1016/S1357-2725(97)00085-X, 2002184, JOURNAL, Karin M, Too many transcription factors: positive and negative interactions, The New Biologist, 2, 2, 126–31, February 1990, 2128034, The function of TFs is to regulate—turn on and off—genes in order to make sure that they are expressed in the right cell 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 up to 2600 TFs in the human genome.TFs work alone or with other proteins in a complex, by promoting (as an activator), or blocking (as a repressor) the recruitment of RNA polymerase (the enzyme that performs the transcription of genetic information from DNA to RNA) to specific genes.JOURNAL, Roeder RG, The role of general initiation factors in transcription by RNA polymerase II, Trends in Biochemical Sciences, 21, 9, 327–35, September 1996, 8870495, 10.1016/S0968-0004(96)10050-5, JOURNAL, Nikolov DB, Burley SK, RNA polymerase II transcription initiation: a structural view, Proceedings of the National Academy of Sciences of the United States of America, 94, 1, 15–22, January 1997, 8990153, 33652, 10.1073/pnas.94.1.15, 1997PNAS...94...15N, JOURNAL, Lee TI, Young RA, Transcription of eukaryotic protein-coding genes, Annual Review of Genetics, 34, 77–137, 2000, 11092823, 10.1146/annurev.genet.34.1.77, 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.JOURNAL, Mitchell PJ, Tjian R, Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins, Science, 245, 4916, 371–8, July 1989, 2667136, 10.1126/science.2667136, 1989Sci...245..371M, JOURNAL, Ptashne M, Gann A, Transcriptional activation by recruitment, Nature, 386, 6625, 569–77, April 1997, 9121580, 10.1038/386569a0, 1997Natur.386..569P, TFs are grouped into classes based on their DBDs.JOURNAL, Jin J, Zhang H, Kong L, Gao G, Luo J, PlantTFDB 3.0: a portal for the functional and evolutionary study of plant transcription factors, Nucleic Acids Research, 42, Database issue, D1182-7, January 2014, 24174544, 3965000, 10.1093/nar/gkt1016, Other proteins such as coactivators, chromatin remodelers, histone acetyltransferases, histone deacetylases, kinases, and methylases are also essential to gene regulation, but lack DNA-binding domains, and therefore are not TFs.JOURNAL, Brivanlou AH, Darnell JE, Signal transduction and the control of gene expression, Science, 295, 5556, 813–8, February 2002, 11823631, 10.1126/science.1066355, 2002Sci...295..813B, TFs are of interest in medicine because TF mutations can cause specific diseases, and medications can be potentially targeted toward them.

Number

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.JOURNAL, van Nimwegen E, Scaling laws in the functional content of genomes, Trends in Genetics, 19, 9, 479–84, September 2003, 12957540, 10.1016/S0168-9525(03)00203-8,weblink physics/0307001, There are approximately 2600 proteins in the human genome that contain DNA-binding domains, and most of these are presumed to function as transcription factors,JOURNAL, Babu MM, Luscombe NM, Aravind L, Gerstein M, Teichmann SA, Structure and evolution of transcriptional regulatory networks, Current Opinion in Structural Biology, 14, 3, 283–91, June 2004, 15193307, 10.1016/j.sbi.2004.05.004,weblink though other studies indicate it to be a smaller number.List Of All Transcription Factors In Human 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). 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 development.

Mechanism

Transcription factors bind to either enhancer or promoter regions of DNA adjacent to the genes that they regulate. Depending on the transcription factor, the transcription of the adjacent gene is either up- or down-regulated. Transcription factors use a variety of mechanisms for the regulation of gene expression.JOURNAL, Gill G, Regulation of the initiation of eukaryotic transcription, Essays in Biochemistry, 37, 33–43, 2001, 11758455, 10.1042/bse0370033, These mechanisms include:
  • stabilize or block the binding of RNA polymerase to DNA
  • 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:JOURNAL, Narlikar GJ, Fan HY, Kingston RE, Cooperation between complexes that regulate chromatin structure and transcription, Cell, 108, 4, 475–87, February 2002, 11909519, 10.1016/S0092-8674(02)00654-2,
    • histone acetyltransferase (HAT) activity – acetylates histone proteins, which weakens the association of DNA with histones, 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 or corepressor proteins to the transcription factor DNA complexJOURNAL, Xu L, Glass CK, Rosenfeld MG, Coactivator and corepressor complexes in nuclear receptor function, Current Opinion in Genetics & Development, 9, 2, 140–7, April 1999, 10322133, 10.1016/S0959-437X(99)80021-5,

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 transcription regulation

In eukaryotes, an important class of transcription factors called general transcription factors (GTFs) are necessary for transcription to occur.BOOK, Robert O. J. Weinzierl, Mechanisms of Gene Expression: Structure, Function and Evolution of the Basal Transcriptional Machinery, World Scientific Publishing Company, 1999, 1-86094-126-5, JOURNAL, Reese JC, Basal transcription factors, Current Opinion in Genetics & Development, 13, 2, 114–8, April 2003, 12672487, 10.1016/S0959-437X(03)00013-3, JOURNAL, Shilatifard A, Conaway RC, Conaway JW, The RNA polymerase II elongation complex, Annual Review of Biochemistry, 72, 693–715, 2003, 12676794, 10.1146/annurev.biochem.72.121801.161551, 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.JOURNAL, Thomas MC, Chiang CM, The general transcription machinery and general cofactors, Critical Reviews in Biochemistry and Molecular Biology, 41, 3, 105–78, 2006, 16858867, 10.1080/10409230600648736, The preinitiation complex binds to 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 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.

Development

Many transcription factors in multicellular organisms are involved in development.JOURNAL, Lobe CG, Transcription factors and mammalian development, Current Topics in Developmental Biology, 27, 351–83, 1992, 1424766, 10.1016/S0070-2153(08)60539-6, 978-0-12-153127-0, Current Topics in Developmental Biology, Responding to stimuli, these transcription factors turn on/off the transcription of the appropriate genes, which, in turn, allows for changes in cell morphology or activities needed for cell fate determination and cellular differentiation. The Hox transcription factor family, for example, is important for proper body pattern formation in organisms as diverse as fruit flies to humans.JOURNAL, Lemons D, McGinnis W, Genomic evolution of Hox gene clusters, Science, 313, 5795, 1918–22, September 2006, 17008523, 10.1126/science.1132040, 2006Sci...313.1918L, JOURNAL, Moens CB, Selleri L, Hox cofactors in vertebrate development, Developmental Biology, 291, 2, 193–206, March 2006, 16515781, 10.1016/j.ydbio.2005.10.032, Another example is the transcription factor encoded by the Sex-determining Region Y (SRY) gene, which plays a major role in determining sex in humans.JOURNAL, Ottolenghi C, Uda M, Crisponi L, Omari S, Cao A, Forabosco A, Schlessinger D, Determination and stability of sex, BioEssays, 29, 1, 15–25, January 2007, 17187356, 10.1002/bies.20515,

Response to intercellular signals

Cells can communicate with each other by releasing molecules that produce 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.JOURNAL, Pawson T, Signal transduction--a conserved pathway from the membrane to the nucleus, Developmental Genetics, 14, 5, 333–8, 1993, 8293575, 10.1002/dvg.1020140502, 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 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 nucleus and binds to its DNA-binding sites, changing the transcriptional regulation of the associated genes.JOURNAL, Osborne CK, Schiff R, Fuqua SA, Shou J, Estrogen receptor: current understanding of its activation and modulation, Clinical Cancer Research, 7, 12 Suppl, 4338s–4342s; discussion 4411s–4412s, December 2001, 11916222,

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,JOURNAL, Shamovsky I, Nudler E, New insights into the mechanism of heat shock response activation, Cellular and Molecular Life Sciences, 65, 6, 855–61, March 2008, 18239856, 10.1007/s00018-008-7458-y, hypoxia inducible factor (HIF), which upregulates genes necessary for cell survival in low-oxygen environments,JOURNAL, Benizri E, Ginouvès A, Berra E, The magic of the hypoxia-signaling cascade, Cellular and Molecular Life Sciences, 65, 7–8, 1133–49, April 2008, 18202826, 10.1007/s00018-008-7472-0, and sterol regulatory element binding protein (SREBP), which helps maintain proper lipid levels in the cell.JOURNAL, Weber LW, Boll M, Stampfl A, Maintaining cholesterol homeostasis: sterol regulatory element-binding proteins, World Journal of Gastroenterology, 10, 21, 3081–7, November 2004, 15457548, 4611246, 10.3748/wjg.v10.i21.3081,weblink

Cell cycle control

Many transcription factors, especially some that are proto-oncogenes or 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.JOURNAL, Wheaton K, Atadja P, Riabowol K, Regulation of transcription factor activity during cellular aging, Biochemistry and Cell Biology, 74, 4, 523–34, 1996, 8960358, 10.1139/o96-056, JOURNAL, Meyyappan M, Atadja PW, Riabowol KT, Regulation of gene expression and transcription factor binding activity during cellular aging, Biological Signals, 5, 3, 130–8, 1996, 8864058, 10.1159/000109183, One example is the Myc oncogene, which has important roles in cell growth and apoptosis.JOURNAL, Evan G, Harrington E, Fanidi A, Land H, Amati B, Bennett M, Integrated control of cell proliferation and cell death by the c-myc oncogene, Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 345, 1313, 269–75, August 1994, 7846125, 10.1098/rstb.1994.0105,

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 effectors) 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.JOURNAL, Boch J, Bonas U, Xanthomonas AvrBs3 family-type III effectors: discovery and function, Annual Review of Phytopathology, 48, 419–36, 2010, 19400638, 10.1146/annurev-phyto-080508-081936, 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.JOURNAL, Moscou MJ, Bogdanove AJ, A simple cipher governs DNA recognition by TAL effectors, Science, 326, 5959, 1501, December 2009, 19933106, 10.1126/science.1178817, 2009Sci...326.1501M, JOURNAL, Boch J, Scholze H, Schornack S, Landgraf A, Hahn S, Kay S, Lahaye T, Nickstadt A, Bonas U, Breaking the code of DNA binding specificity of TAL-type III effectors, Science, 326, 5959, 1509–12, December 2009, 19933107, 10.1126/science.1178811, 2009Sci...326.1509B, This property likely makes it easier for these proteins to evolve in order to better compete with the defense mechanisms of the host cell.JOURNAL, Voytas DF, Joung JK, Plant science. DNA binding made easy, Science, 326, 5959, 1491–2, December 2009, 20007890, 10.1126/science.1183604, 2009Sci...326.1491V,

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.JOURNAL, Pan G, Li J, Zhou Y, Zheng H, Pei D, A negative feedback loop of transcription factors that controls stem cell pluripotency and self-renewal, FASEB Journal, 20, 10, 1730–2, August 2006, 16790525, 10.1096/fj.05-5543fje,

Nuclear localization

In eukaryotes, transcription factors (like most proteins) are transcribed in the nucleus but are then translated in the cell's cytoplasm. Many proteins that are active in the nucleus contain nuclear localization signals that direct them to the nucleus. But, for many transcription factors, this is a key point in their regulation.JOURNAL, Whiteside ST, Goodbourn S, Signal transduction and nuclear targeting: regulation of transcription factor activity by subcellular localisation, Journal of Cell Science, 104, 4, 949–55, April 1993, 8314906, Important classes of transcription factors such as some nuclear receptors must first bind a ligand while in the cytoplasm before they can relocate to the nucleus.

Activation

Transcription factors may be activated (or deactivated) through their signal-sensing domain by a number of mechanisms including:
  • 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 receptors).
  • phosphorylationJOURNAL, Bohmann D, Transcription factor phosphorylation: a link between signal transduction and the regulation of gene expression, Cancer Cells, 2, 11, 337–44, November 1990, 2149275, JOURNAL, Weigel NL, Moore NL, Steroid receptor phosphorylation: a key modulator of multiple receptor functions, Molecular Endocrinology, 21, 10, 2311–9, October 2007, 17536004, 10.1210/me.2007-0101, – Many transcription factors such as STAT proteins must be phosphorylated before they can bind DNA.
  • interaction with other transcription factors (e.g., homo- or hetero-dimerization) or coregulatory proteins

Accessibility of DNA-binding site

In eukaryotes, DNA is organized with the help of histones into compact particles called nucleosomes, 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 pioneering factors 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 remodelers.JOURNAL, Teif VB, Rippe K, Predicting nucleosome positions on the DNA: combining intrinsic sequence preferences and remodeler activities, Nucleic Acids Research, 37, 17, 5641–55, September 2009, 19625488, 2761276, 10.1093/nar/gkp610, 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 compete for binding to its DNA binding site with other transcription factors and histones or non-histone chromatin proteins.JOURNAL, Teif VB, Rippe K, Statistical-mechanical lattice models for protein-DNA binding in chromatin, Journal of Physics: Condensed Matter, 22, 41, 414105, October 2010, 21386588, 10.1088/0953-8984/22/41/414105, 1004.5514, 2010JPCM...22O4105T, Pairs of transcription factors and other proteins can play antagonistic roles (activator versus repressor) in the regulation of the same gene.

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.JOURNAL, Amoutzias GD, Robertson DL, Van de Peer Y, Oliver SG, Choose your partners: dimerization in eukaryotic transcription factors, Trends in Biochemical Sciences, 33, 5, 220–9, May 2008, 18406148, 10.1016/j.tibs.2008.02.002, 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 cofactors that allow efficient recruitment of the 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.JOURNAL, Copland JA, Sheffield-Moore M, Koldzic-Zivanovic N, Gentry S, Lamprou G, Tzortzatou-Stathopoulou F, Zoumpourlis V, Urban RJ, Vlahopoulos SA, Sex steroid receptors in skeletal differentiation and epithelial neoplasia: is tissue-specific intervention possible?, BioEssays, 31, 6, 629–41, June 2009, 19382224, 10.1002/bies.200800138,

Structure

(File:Transcription factor schematic 2.png|thumb|400px|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 a transactivation domain (TAD). 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.)Transcription factors are modular in structure and contain the following domains:
  • DNA-binding domain (DBD), which attaches to specific sequences of DNA (enhancer or promoter. Necessary component for all vectors. Used to drive transcription of the vector's transgene promoter sequences) adjacent to regulated genes. DNA sequences that bind transcription factors are often referred to as response elements.
  • Trans-activating domain (TAD), which contains binding sites for other proteins such as transcription coregulators. These binding sites are frequently referred to as activation functions (AFs).JOURNAL, Wärnmark A, Treuter E, Wright AP, Gustafsson JA, Activation functions 1 and 2 of nuclear receptors: molecular strategies for transcriptional activation, Molecular Endocrinology, 17, 10, 1901–9, October 2003, 12893880, 10.1210/me.2002-0384,
  • 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.

Trans-activating domain

The TAD is a domain of the transcription factor that binds other proteins such as transcription coregulators. Proteins containing TADs are Gal4, Gcn4, Oaf1, Leu3, Rtg3, Pho4, Gln3 in yeast and p53, NFAT, NF-κB and VP16 in mammals.JOURNAL, Piskacek S, Gregor M, Nemethova M, Grabner M, Kovarik P, Piskacek M, Nine-amino-acid transactivation domain: establishment and prediction utilities, Genomics, 89, 6, 756–68, June 2007, 17467953, 10.1016/j.ygeno.2007.02.003, Many TADs are as short as 9 amino acids (present in e.g., p53, VP16, MLL, E2A, HSF1, NF-IL6, NFAT1 and NF-κB Gal4, Pdr1, Oaf1, Gcn4, VP16, Pho4, Msn2, Ino2 and P201).

DNA-binding domain

File:LacI Dimer Structure Annotated.png|thumb|300px|right|Domain architecture example: Lactose Repressor (LacI). The N-terminal DNA binding domain (labeled) of the lac repressor binds its target DNA sequence (gold) in the major groove using a helix-turn-helixhelix-turn-helixThe portion (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;"| SCOP
basic helix-loop-helixLITTLEWOOD TD, EVAN GI JOURNAL = PROTEIN PROFILE ISSUE = 6 YEAR = 1995 DOI =, IPR001092}}PF00010}}47460}}
bZIP domain>bZIP)VINSON C, MYAKISHEV M, ACHARYA A, MIR AA, MOLL JR, BONOVICH M > TITLE = CLASSIFICATION OF HUMAN B-ZIP PROTEINS BASED ON DIMERIZATION PROPERTIES VOLUME = 22 PAGES = 6321–35 PMID = 12192032 DOI = 10.1128/MCB.22.18.6321-6335.2002, IPR004827}}PF00170}}57959}}
| C-terminal effector domain of the bipartite response regulators
IPR001789}}PF00072}}46894}}
| AP2/ERF/GCC box
IPR001471}}PF00847}}54176}}
helix-turn-helixWINTJENS R, ROOMAN M JOURNAL = JOURNAL OF MOLECULAR BIOLOGY ISSUE = 2 DATE = SEPTEMBER 1996 DOI = 10.1006/JMBI.1996.0514, | | |
homeodomain fold>homeodomain proteins, which are encoded by homeobox genes, are transcription factors. Homeodomain proteins play critical roles in the regulation of developmental biology.GEHRING WJ, AFFOLTER M, BüRGLIN T JOURNAL = ANNUAL REVIEW OF BIOCHEMISTRY ISSUE = YEAR = 1994 DOI = 10.1146/ANNUREV.BI.63.070194.002415, BüRGLIN TR, AFFOLTER M > TITLE = HOMEODOMAIN PROTEINS: AN UPDATE VOLUME = 125 PAGES = 497–521 PMID = 26464018 DOI = 10.1007/S00412-015-0543-8,weblink IPR009057}}PF00046}}46689}}
CI protein>lambda repressor-likeIPR010982}}| 47413}}
| srf-like (serum response factor)
IPR002100}}PF00319}}55455}}
pax genes>paired boxDAHL E, KOSEKI H, BALLING R > TITLE = PAX GENES AND ORGANOGENESIS VOLUME = 19 PAGES = 755–65 PMID = 9297966, 10.1002/bies.950190905, | | |
| winged helix
IPR013196}}PF08279}}46785}}
zinc fingersLAITY JH, LEE BM, WRIGHT PE JOURNAL = CURRENT OPINION IN STRUCTURAL BIOLOGY ISSUE = 1 DATE = FEBRUARY 2001 DOI = 10.1016/S0959-440X(00)00167-6, | | |
JOURNAL = ANNUAL REVIEW OF BIOPHYSICS AND BIOMOLECULAR STRUCTURE ISSUE = YEAR = 2000 DOI = 10.1146/ANNUREV.BIOPHYS.29.1.183, IPR007087}}PF00096}}57667}}
| * Zn2/Cys6| |
57701}}
| * Zn2/Cys8 nuclear receptor zinc finger
IPR001628}}PF00105}}57716}}

Response elements

The DNA sequence that a transcription factor binds to is called a transcription factor-binding site or response element.JOURNAL, Wang JC, Finding primary targets of transcriptional regulators, Cell Cycle, 4, 3, 356–8, March 2005, 15711128, 10.4161/cc.4.3.1521,weblink Transcription factors interact with their binding sites using a combination of electrostatic (of which hydrogen bonds are a special case) and Van der Waals forces. Due to the nature of these chemical interactions, most transcription factors bind DNA in a sequence specific manner. However, not all 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.For example, although the 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.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. Other constraints, such as DNA accessibility in the cell or availability of 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 mutations in transcription factors.BOOK, Semenza, Gregg L., Transcription factors and human disease, Oxford University Press, Oxford [Oxfordshire], 1999, 978-0-19-511239-9, Many transcription factors are either tumor suppressors or oncogenes, 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 families, (2) the STAT family and (3) the steroid receptors.JOURNAL, Libermann TA, Zerbini LF, Targeting transcription factors for cancer gene therapy, Current Gene Therapy, 6, 1, 17–33, February 2006, 16475943, 10.2174/156652306775515501, Below are a few of the better-studied examples:{| class="wikitable"! Condition! Description! Locus
| Rett syndrome
MECP2 transcription factor are associated with Rett syndrome, a neurodevelopmental disorder.MORETTI P, ZOGHBI HY JOURNAL = CURRENT OPINION IN GENETICS & DEVELOPMENT ISSUE = 3 DATE = JUNE 2006 DOI = 10.1016/J.GDE.2006.04.009, CHADWICK LH, WADE PA > TITLE = MECP2 IN RETT SYNDROME: TRANSCRIPTIONAL REPRESSOR OR CHROMATIN ARCHITECTURAL PROTEIN? VOLUME = 17 PAGES = 121–5 PMID = 17317146, 10.1016/j.gde.2007.02.003, | Xq28
| Diabetes
diabetes called MODY (Maturity onset diabetes of the young) can be caused by mutations in hepatocyte nuclear factors (HNFs)MAESTRO MA, CARDALDA C, BOJ SF, LUCO RF, SERVITJA JM, FERRER J JOURNAL = ENDOCRINE DEVELOPMENT ISSUE = YEAR = 2007 DOI = 10.1159/000109603 Pdx1>insulin promoter factor-1 (IPF1/Pdx1).AL-QUOBAILI F, MONTENARH M > TITLE = PANCREATIC DUODENAL HOMEOBOX FACTOR-1 AND DIABETES MELLITUS TYPE 2 (REVIEW) VOLUME = 21 PAGES = 399–404 PMID = 18360684 URL = HTTP://WWW.SPANDIDOS-PUBLICATIONS.COM/IJMM/ARTICLE.JSP?ARTICLE_ID=IJMM_21_4_399, | multiple
Apraxia of speech#Childhood apraxia of speech>Developmental verbal dyspraxiaFOXP2 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.LENNON PA, COOPER ML, PEIFFER DA, GUNDERSON KL, PATEL A, PETERS S, CHEUNG SW, BACINO CA > TITLE = DELETION OF 7Q31.1 SUPPORTS INVOLVEMENT OF FOXP2 IN LANGUAGE IMPAIRMENT: CLINICAL REPORT AND REVIEW VOLUME = 143A PAGES = 791–8 PMID = 17330859, 10.1002/ajmg.a.31632, | 7q31
| Autoimmune diseases
FOXP3 transcription factor cause a rare form of autoimmune disease called IPEX (syndrome)>IPEX.VAN DER VLIET HJ, NIEUWENHUIS EE > TITLE = IPEX AS A RESULT OF MUTATIONS IN FOXP3 VOLUME = 2007 PAGES = 1–5 PMID = 18317533 DOI = 10.1155/2007/89017, | Xp11.23-q13.3
| Li-Fraumeni syndrome
p53 (protein)>p53.IWAKUMA T, LOZANO G, FLORES ER > TITLE = LI-FRAUMENI SYNDROME: A P53 FAMILY AFFAIR VOLUME = 4 PAGES = 865–7 PMID = 15917654 URL = HTTP://WWW.LANDESBIOSCIENCE.COM/JOURNALS/CC/ABSTRACT.PHP?ID=1800, | 17p13.1
| Breast cancer
STAT protein>STAT family is relevant to breast cancer.weblink" title="archive.is/20041107221936weblink">"Roles and Regulation of Stat Family Transcription Factors in Human Breast Cancer" 2004| multiple
| Multiple cancers
HOX gene>HOX family are involved in a variety of cancers."Transcription factors as targets and markers in cancer" Workshop 2007| multiple

Potential drug targets

{{see also|Therapeutic gene modulation}}Approximately 10% of currently prescribed drugs directly target the nuclear receptor class of transcription factors.JOURNAL, Overington JP, Al-Lazikani B, Hopkins AL, How many drug targets are there?, Nature Reviews. Drug Discovery, 5, 12, 993–6, December 2006, 17139284, 10.1038/nrd2199, Examples include tamoxifen and bicalutamide for the treatment of breast and prostate cancer, respectively, and various types of anti-inflammatory and anabolic steroids.JOURNAL, Gronemeyer H, Gustafsson JA, Laudet V, Principles for modulation of the nuclear receptor superfamily, Nature Reviews. Drug Discovery, 3, 11, 950–64, November 2004, 15520817, 10.1038/nrd1551, In addition, transcription factors are often indirectly modulated by drugs through signaling cascades. It might be possible to directly target other less-explored transcription factors such as NF-κB with drugs.JOURNAL, Bustin SA, McKay IA, Transcription factors: targets for new designer drugs, British Journal of Biomedical Science, 51, 2, 147–57, June 1994, 8049612, JOURNAL, Butt TR, Karathanasis SK, Transcription factors as drug targets: opportunities for therapeutic selectivity, Gene Expression, 4, 6, 319–36, 1995, 7549464, JOURNAL, Papavassiliou AG, Transcription-factor-modulating agents: precision and selectivity in drug design, Molecular Medicine Today, 4, 8, 358–66, August 1998, 9755455, 10.1016/S1357-4310(98)01303-3, JOURNAL, Ghosh D, Papavassiliou AG, Transcription factor therapeutics: long-shot or lodestone, Current Medicinal Chemistry, 12, 6, 691–701, 2005, 15790306, 10.2174/0929867053202197, 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 "drugable" but progress has been made on Pax2JOURNAL, Grimley E, Liao C, Ranghini E, Nikolovska-Coleska Z, Dressler G, Inhibition of Pax2 Transcription Activation with a Small Molecule that Targets the DNA Binding Domain, ACS Chemical Biology, 12, 3, 724–734, 2017, 28094913, 10.1021/acschembio.6b00782, JOURNAL, Grimley E, Dressler GR, Are Pax proteins potential therapeutic targets in kidney disease and cancer?, Kidney International, 2018, 29685496, 10.1016/j.kint.2018.01.025, and the notch pathway.JOURNAL, Moellering RE, Cornejo M, Davis TN, Del Bianco C, Aster JC, Blacklow SC, Kung AL, Gilliland DG, Verdine GL, Bradner JE, Direct inhibition of the NOTCH transcription factor complex, Nature, 462, 7270, 182–8, November 2009, 19907488, 2951323, 10.1038/nature08543,weblink The Scientist, 2009Natur.462..182M,

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.JOURNAL, 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, A promiscuous intermediate underlies the evolution of LEAFY DNA binding specificity, Science, 343, 6171, 645–8, February 2014, 24436181, 10.1126/science.1248229, 2014Sci...343..645S, JOURNAL, Jin J, He K, Tang X, Li Z, Lv L, Zhao Y, Luo J, Gao G, An Arabidopsis Transcriptional Regulatory Map Reveals Distinct Functional and Evolutionary Features of Novel Transcription Factors, Molecular Biology and Evolution, 32, 7, 1767–73, July 2015, 25750178, 4476157, 10.1093/molbev/msv058,

Analysis

There are different technologies available to analyze transcription factors. On the genomic level, DNA-sequencingEntrezGene database and database research are commonly usedJOURNAL, Grau J, Ben-Gal I, Posch S, Grosse I, VOMBAT: prediction of transcription factor binding sites using variable order Bayesian trees, Nucleic Acids Research, 34, Web Server issue, W529-33, July 2006, 16845064, 1538886, 10.1093/nar/gkl212,weblink 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),JOURNAL, Wenta N, Strauss H, Meyer S, Vinkemeier U, Tyrosine phosphorylation regulates the partitioning of STAT1 between different dimer conformations, Proceedings of the National Academy of Sciences of the United States of America, 105, 27, 9238–43, July 2008, 18591661, 2453697, 10.1073/pnas.0802130105, 2008PNAS..105.9238W, the activation profile of transcription factors can be detected. A multiplex approach for activation profiling is a TF chip system where several different transcription factors can be detected in parallel.The most commonly used method for identifying transcription factor binding sites is chromatin immunoprecipitation (ChIP).JOURNAL, Furey TS, ChIP-seq and beyond: new and improved methodologies to detect and characterize protein-DNA interactions, Nature Reviews. Genetics, 13, 12, 840–52, December 2012, 23090257, 3591838, 10.1038/nrg3306, 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-seq) to determine transcription factor binding sites. If no antibody is available for the protein of interest, DamID may be a convenient alternative.JOURNAL, Aughey GN, Southall TD, Dam it's good! DamID profiling of protein-DNA interactions, Wiley Interdisciplinary Reviews: Developmental Biology, 5, 1, 25–37, January 2016, 26383089, 4737221, 10.1002/wdev.205,

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.

Mechanistic

There are two mechanistic classes of transcription factors:
  • General transcription factors are involved in the formation of a 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 genes.JOURNAL, Orphanides G, Lagrange T, Reinberg D, The general transcription factors of RNA polymerase II, Genes & Development, 10, 21, 2657–83, November 1996, 8946909, 10.1101/gad.10.21.2657,
  • 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 sequences are present in the proximity of the gene.BOOK, Walter F., Boron, vanc, Medical Physiology: A Cellular And Molecular Approaoch, Elsevier/Saunders, 2003, 125–126, 1-4160-2328-3,
{|class="wikitable"!colspan=4| Examples of specific transcription factors! Factor !! Structural type !! Recognition sequence !! Binds as
! SP1
Zinc finger >five prime end>5'-GGGCGG-three prime end >| Monomer
! AP-1
Basic zipper >| Dimer
! C/EBP
Basic zipper >| Dimer
! Heat shock factor
Basic zipper >| Trimer
! ATF/CREB
Basic zipper >| Dimer
! c-Myc | Basic helix-loop-helix
| Dimer
! Oct-1
Helix-turn-helix >| Monomer
! NF-1
| Dimer
(G/C) = G or C X = adenine, thymine>T, guanine or cytosine>C

Functional

Transcription factors have been classified according to their regulatory function:
  • I. constitutively active – present in all cells at all times – general transcription factors, Sp1, NF1, CCAAT
  • II. conditionally active – requires activation
    • II.A developmental (cell specific) – expression is tightly controlled, but, once expressed, require no additional activation – GATA, HNF, PIT-1, MyoD, Myf5, Hox, Winged Helix
    • II.B signal-dependent – requires external signal for activation
      • II.B.1 extracellular ligand (endocrine or paracrine)-dependent – nuclear receptors
      • II.B.2 intracellular ligand (autocrine)-dependent - activated by small intracellular molecules – SREBP, p53, orphan nuclear receptors
      • II.B.3 cell membrane receptor-dependent – second messenger signaling cascades resulting in the phosphorylation of the transcription factor
II.B.3.a resident nuclear factors – reside in the nucleus regardless of activation state – CREB, AP-1, Mef2 II.B.3.b latent cytoplasmic factors – inactive form reside in the cytoplasm, but, when activated, are translocated into the nucleus – STAT, R-SMAD, NF-κB, Notch, TUBBY, NFAT

Structural

Transcription factors are often classified based on the sequence similarity and hence the tertiary structure of their DNA-binding domains:JOURNAL, Stegmaier P, Kel AE, Wingender E, Systematic DNA-binding domain classification of transcription factors, Genome Informatics. International Conference on Genome Informatics, 15, 2, 276–86, 2004, 15706513,weblinkweblink" title="web.archive.org/web/20130619202726weblink">weblink yes, 19 June 2013, JOURNAL, 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, TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes, Nucleic Acids Research, 34, Database issue, D108-10, January 2006, 16381825, 1347505, 10.1093/nar/gkj143, WEB, TRANSFAC database,weblink 5 August 2007,
  • 1 Superclass: Basic Domains
    • 1.1 Class: Leucine zipper factors (bZIP)
      • 1.1.1 Family: AP-1(-like) components; includes (c-Fos/c-Jun)
      • 1.1.2 Family: CREB
      • 1.1.3 Family: C/EBP-like factors
      • 1.1.4 Family: bZIP / 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 (bHLH-ZIP)
      • 1.3.1 Family: Ubiquitous bHLH-ZIP factors; includes USF (USF1, USF2); SREBP (SREBP)
      • 1.3.2 Family: Cell-cycle controlling factors; includes c-Myc
    • 1.4 Class: NF-1
      • 1.4.1 Family: NF-1 (A, B, C, X)
    • 1.5 Class: RF-X
      • 1.5.1 Family: RF-X (1, 2, 3, 4, 5, ANK)
    • 1.6 Class: bHSH
  • 2 Superclass: Zinc-coordinating DNA-binding domains
  • 3 Superclass: Helix-turn-helix
    • 3.1 Class: Homeo domain
      • 3.1.1 Family: Homeo domain only; includes Ubx
      • 3.1.2 Family: POU domain factors; includes 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: Fork head / 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 Factors
      • 3.4.1 Family: HSF
    • 3.5 Class: Tryptophan clusters
    • 3.6 Class: TEA ( transcriptional enhancer factor) domain
  • 4 Superclass: beta-Scaffold Factors with Minor Groove Contacts
    • 4.1 Class: RHR (Rel homology region)
    • 4.2 Class: STAT
    • 4.3 Class: p53
      • 4.3.1 Family: p53
    • 4.4 Class: 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 proteins
      • 4.6.1 Family: TBP
    • 4.7 Class: HMG-box
      • 4.7.1 Family: SOX genes, SRY
      • 4.7.2 Family: TCF-1 (TCF1)
      • 4.7.3 Family: HMG2-related, 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: AP2
      • 0.5.2 Family: EREBP
      • 0.5.3 Superfamily: AP2/B3
0.5.3.1 Family: ARF0.5.3.2 Family: ABI0.5.3.3 Family: RAV

See also

{{colbegin|colwidth=30em}} {{colend}}

References

{{reflist|33em}}

Further reading

  • JOURNAL, Jin J, He K, Tang X, Li Z, Lv L, Zhao Y, Luo J, Gao G, An Arabidopsis Transcriptional Regulatory Map Reveals Distinct Functional and Evolutionary Features of Novel Transcription Factors, Molecular Biology and Evolution, 32, 7, 1767–73, 2015, 25750178, 4476157, 10.1093/molbev/msv058,
  • JOURNAL, Lambert S, Jolma A, Campitelli L, Pratyush Z, Das K, Yin Y, Albu M, Chen X, Taipae J, Hughes T, Weirauch M, The Human Transcription Factors, Cell, 172, 4, 650–665, 2018, 10.1016/j.cell.2018.01.029,

External links

{{Cell signaling}}{{Transcription factors}}{{genarch}}

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