- Transcription factor
In the field of
molecular biology, a transcription factor (sometimes called a sequence-specific DNA binding factor) is a proteinthat binds to specific sequences of DNAand thereby controls the transfer (or transcription) of genetic information from DNA to RNA.cite journal | author = Latchman DS | title = Transcription factors: an overview | journal = Int. J. Biochem. Cell Biol. | volume = 29 | issue = 12 | pages = 1305–12 | year = 1997 | pmid = 9570129 | doi = 10.1016/S1357-2725(97)00085-X ] cite journal | author = Karin M | title = Too many transcription factors: positive and negative interactions | journal = New Biol. | volume = 2 | issue = 2 | pages = 126–31 | year = 1990 | pmid = 2128034 | doi = | issn = ] Transcription factors perform this function 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 which activates the transcription of genetic information from DNA to RNA) to specific genes.cite journal | author = Roeder RG | title = The role of general initiation factors in transcription by RNA polymerase II | journal = Trends Biochem. Sci. | volume = 21 | issue = 9 | pages = 327–35 | year = 1996 | pmid = 8870495 | doi = 10.1016/0968-0004(96)10050-5 ] cite journal | author = Nikolov DB, Burley SK | title = RNA polymerase II transcription initiation: a structural view | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 94 | issue = 1 | pages = 15–22 | year = 1997 | pmid = 8990153 | doi = 10.1073/pnas.94.1.15 ] cite journal | author = Lee TI, Young RA | title = Transcription of eukaryotic protein-coding genes | journal = Annu. Rev. Genet. | volume = 34 | issue = | pages = 77–137 | year = 2000 | pmid = 11092823 | doi = 10.1146/annurev.genet.34.1.77]
A defining feature of transcription factors is that they contain one or more
DNA binding domains (DBDs) which attach to specific sequences of DNA adjacent to the genes that they regulate.cite journal | author = Mitchell PJ, Tjian R | title = Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins | journal = Science | volume = 245 | issue = 4916 | pages = 371-8 | year = 1989 | pmid = 2667136 | doi = 10.1126/science.2667136 | issn = ] cite journal | author = Ptashne M, Gann A | title = Transcriptional activation by recruitment | journal = Nature | volume = 386 | issue = 6625 | pages = 569-77 | year = 1997 | pmid = 9121580 | doi = 10.1038/386569a0 | issn = ] Additional proteins such as coactivators, chromatin remodelers, histone acetylases, deacetylases, kinases, and methylases, while also playing crucial roles in gene regulation, lack DNA binding domains, and therefore are not classified as transcription factors.cite journal | author = Brivanlou AH, Darnell JE | title = Signal transduction and the control of gene expression | journal = Science | volume = 295 | issue = 5556 | pages = 813-8 | year = 2002 | pmid = 11823631 | doi = 10.1126/science.1066355 | issn = ]
Conservation in different organisms
Transcription factors are essential for the regulation of gene expression and consequently are found in all living organisms. The number of transcription factors found within an organism increases with the genome size and the larger genomes tend to have more transcription factors per gene.cite journal | author = van Nimwegen E | title = Scaling laws in the functional content of genomes | journal = Trends Genet. | volume = 19 | issue = 9 | pages = 479–84 | year = 2003 | pmid = 12957540 | doi = 10.1016/S0168-9525(03)00203-8 ]
There are approximately 2600 proteins in the
human genomethat contain DNA-binding domains and most of these are presumed to function as transcription factors.cite journal | author = Babu MM, Luscombe NM, Aravind L, Gerstein M, Teichmann SA | title = Structure and evolution of transcriptional regulatory networks | journal = Curr. Opin. Struct. Biol. | volume = 14 | issue = 3 | pages = 283–91 | year = 2004 | pmid = 15193307 | doi = 10.1016/j.sbi.2004.05.004 ] 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.
Transcription factors are one of the groups of proteins that read and interpret the genetic "blueprint" in the DNA. They bind 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
eukaryotes, an important class of transcription factors called general transcription factors (GTFs) are necessary for transcription to occur.cite journal | author = Reese JC | title = Basal transcription factors | journal = Current opinion in genetics & development | volume = 13 | issue = 2 | pages = 114–8 | year = 2003 | month = April | pmid = 12672487 | doi = 10.1016/S0959-437X(03)00013-3 | url = | issn = ] cite journal | author = Shilatifard A, Conaway RC, Conaway JW | title = The RNA polymerase II elongation complex | journal = Annual review of biochemistry | volume = 72 | issue = | pages = 693–715 | year = 2003 | pmid = 12676794 | doi = 10.1146/annurev.biochem.72.121801.161551 | url = | issn = ] Many of these GTFs don't actually bind DNA but are part of the large transcription preinitiation complexthat interacts with RNA polymerasedirectly. The most common GTFs are TFIIA, TFIIB, TFIID(see also TATA binding protein), TFIIE, TFIIF, and TFIIH.cite journal | author = Thomas MC, Chiang CM | title = The general transcription machinery and general cofactors | journal = Critical reviews in biochemistry and molecular biology | volume = 41 | issue = 3 | pages = 105–78 | year = 2006 | pmid = 16858867 | doi = | url = | issn = ]
Many transcription factors in
multicellular organisms are involved in development.cite journal | author = Lobe CG | title = Transcription factors and mammalian development | journal = Current topics in developmental biology | volume = 27 | issue = | pages = 351–83 | year = 1992 | pmid = 1424766 | doi = | url = | issn = ] Responding to cues (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 determinationand cellular differentiation. The Hoxtranscription factor family, for example, is important for proper body pattern formation in organisms as diverse as fruit flies to humans.cite journal | author = Lemons D, McGinnis W | title = Genomic evolution of Hox gene clusters | journal = Science (New York, N.Y.) | volume = 313 | issue = 5795 | pages = 1918–22 | year = 2006 | month = September | pmid = 17008523 | doi = 10.1126/science.1132040 | url = | issn = ] cite journal | author = Moens CB, Selleri L | title = Hox cofactors in vertebrate development | journal = Developmental biology | volume = 291 | issue = 2 | pages = 193–206 | year = 2006 | month = March | pmid = 16515781 | doi = 10.1016/j.ydbio.2005.10.032 | url = | issn = ] Another example is the transcription factor encoded by the Sex-determining Region Y (SRY) gene which plays a major role in determining gender in humans.cite journal | author = Ottolenghi C, Uda M, Crisponi L, Omari S, Cao A, Forabosco A, Schlessinger D | title = Determination and stability of sex | journal = BioEssays : news and reviews in molecular, cellular and developmental biology | volume = 29 | issue = 1 | pages = 15–25 | year = 2007 | month = January | pmid = 17187356 | doi = 10.1002/bies.20515 | url = | issn = ]
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.
Estrogensignaling is an example of a fairly short signaling cascade that involves the estrogen receptortranscription factor: estrogen is secreted by tissues such as the ovaries and placenta, crosses the cell membraneof 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.
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, hypoxia inducible factor(HIF) which upregulates genes necessary for cell survival in low oxygen environments, and sterol regulatory element binding protein(SREBP) which helps maintain proper lipidlevels in the cell.
Cell cycle control
Many transcription factors, especially some that are
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. One example is the Myconcogene, which has important roles in cell growthand apoptosis.
It is common in biology for important processes to have multiple layers of regulation and control. This 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:
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. One interesting 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 will down-regulate the production of more of itself. This is one mechanism to maintain low levels of a transcription factor in a cell.
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.cite journal | author = Whiteside ST, Goodbourn S | title = Signal transduction and nuclear targeting: regulation of transcription factor activity by subcellular localisation | journal = Journal of cell science | volume = 104 ( Pt 4) | issue = | pages = 949–55 | year = 1993 | month = April | pmid = 8314906 | doi = | url = http://jcs.biologists.org/cgi/pmidlookup?view=long&pmid=8314906 | issn = ] Important classes of transcription factors such as some nuclear receptors must first bind a ligandwhile in the cytoplasm before they can relocate to the nucleus.cite journal | author = Whiteside ST, Goodbourn S | title = Signal transduction and nuclear targeting: regulation of transcription factor activity by subcellular localisation | journal = Journal of cell science | volume = 104 ( Pt 4) | issue = | pages = 949–55 | year = 1993 | month = April | pmid = 8314906 | doi = | url = http://jcs.biologists.org/cgi/pmidlookup?view=long&pmid=8314906 | issn = ]
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 this can also affect whether the transcription factor is in an active state and capable of binding DNA or other cofactors (see for example
phosphorylationcite journal | author = Bohmann D | title = Transcription factor phosphorylation: a link between signal transduction and the regulation of gene expression | journal = Cancer cells (Cold Spring Harbor, N.Y. : 1989) | volume = 2 | issue = 11 | pages = 337–44 | year = 1990 | month = November | pmid = 2149275 | doi = | url = | issn = ] cite journal | author = Weigel NL, Moore NL | title = Steroid Receptor Phosphorylation: A Key Modulator of Multiple Receptor Functions | journal = | volume = |issue = | pages = | year = 2007 | pmid = 17536004 | doi = 10.1210/me.2007-0101 | issn = ] – 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, genes that are not being actively transcribed are often located in
heterochromatin. Heterochromatin are regions of chromosomes that are heavily compacted by tightly bundling the DNA onto histones and then organizing the histones into compact chromatinfibers. DNA within heterochromatin is inaccessible to many transcription factors. For the transcription factor to bind to its DNA binding site the heterochromatin must be first converted to euchromatin, usually via histone modifications. A transcription factor's DNA binding site may also be inaccessible if the site is already occupied by another transcription factor. Pairs of transcription factors can play antagonistic roles (activator versus repressor) in the regulation of the same gene.
Availability of other cofactors/transcription factors
Most transcription factors don't work alone. Often 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 complexand 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.
Transcription factors are modular in structure and contain the following domains:
DNA-binding domain(DBD) which attach to specific sequences of DNA (enhancer or promotersequences) adjacent to regulated genes. DNA sequences which bind transcription factors are often referred to as response elements.
* Trans-activating domain (TAD) which contain binding sites for other proteins such as
transcription coregulators. These binding sites are frequently referred to as activation functions (AFs).cite journal | author = Wärnmark A, Treuter E, Wright AP, Gustafsson J-Å | title = Activation functions 1 and 2 of nuclear receptors: molecular strategies for transcriptional activation | journal = Mol. Endocrinol. | volume = 17 | issue = 10 | pages = 1901–9 | year = 2003 | pmid = 12893880 | doi = 10.1210/me.2002-0384 ]
* An optional signal sensing domain (SSD) ("e.g.", a ligand binding domain) which senses external signals and in response transmit these signals to the rest of the transcription complex resulting in up or down regulation of gene expression. Alternatively the DBD and signal sensing domains may reside on separate proteins that associate within the transcription complex to regulate gene expression.
DNA binding domain
The 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:
The DNA sequence that a transcription factor binds to is called a transcription factor binding site or
Chemically, 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 don't 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 binds all compatible sequences in the
genomeof 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) which bind to two or more adjacent sequences of DNA.
Due to their important roles in development, intercellular signaling, and cell cycle, some human diseases have been associated with
mutations in transcription factors. Below are a few of the more well-studied examples:
* Rett syndrome Mutations in the
MECP2transcription factor are associated with Rett syndrome, a neurodevelopmental disorder.
* Diabetes A rare form of
diabetescalled MODY(Maturity onset diabetes of the young) can be caused by mutations in hepatocyte nuclear factors(HNFs) or insulin promoter factor-1(IPF1).
* Developmental verbal dyspraxia Mutations in the
FOXP2transcription factor are associated with developmental verbal dyspraxia, a disease in which individuals are unable to produce the finely coordinated movements required for speech.
* Autoimmune diseases Mutations in the
FOXP3transcription factor cause a rare form of autoimmune diseasecalled IPEX.
* Cancer Many transcription factors are tumor suppressors or oncogenes, and thus mutations or aberrant regulation of them are associated with cancer. For example,
Li-Fraumeni syndromeis caused by mutations in the tumor suppressor p53.
As described in more detail below, transcription factors may be classified by their (1) mechanism of action, (2) regulatory function, or (3) sequence homology in their DNA binding domains.
There are three 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.cite journal | author = Orphanides G, Lagrange T, Reinberg D | title = The general transcription factors of RNA polymerase II | journal = Genes Dev. | volume = 10 | issue = 21 |pages = 2657–83 | year = 1996 | pmid = 8946909 | doi = 10.1101/gad.10.21.2657 ]
*Upstream transcription factors are proteins that bind somewhere upstream of the initiation site to stimulate or repress transcription.
*Inducible transcription factors are similar to upstream transcription factors but require activation or inhibition.
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-dependent -
*** II.B.2 intracellular ligand-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-kB, Notch, TUBBY, NFAT
Transcription factors are often classified based on the sequence similarity and hence the
tertiary structureof their DNA binding domains:cite journal | author = Stegmaier P, Kel AE, Wingender E | title = Systematic DNA-binding domain classification of transcription factors | journal = Genome informatics. International Conference on Genome Informatics | volume = 15 | issue = 2 | pages = 276–86 | year = 2004 | pmid = 15706513 | doi = | issn = | url = http://www.jsbi.org/journal/GIW04/GIW04F028.html ] cite journal | author = 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 | title = TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes | journal = Nucleic Acids Res. | volume = 34 | issue = Database issue | pages = D108–10 | year = 2006 | pmid = 16381825 | doi = 10.1093/nar/gkj143 ] [cite web|title=TRANSFAC® database|url=http://www.gene-regulation.com/pub/databases/transfac/cl.html|accessdate = 2007-08-05]
*1 Superclass: Basic Domains (
Leucine zipperfactors ( bZIP)
***1.1.1 Family: AP-1(-like) components; includes (
***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 (
***1.2.1 Family: Ubiquitous (class A) factors
***1.2.2 Family: Myogenic transcription factors (
***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 (NFIC)
**1.5 Class: RF-X
***1.5.1 Family: RF-X (gene|NFX2, gene|NFX3, gene|NFX5)
**1.6 Class: bHSH
*2 Superclass: Zinc-coordinating DNA-binding domains
**2.1 Class: Cys4
zinc fingerof nuclear receptortype
Steroid hormone receptors
Thyroid hormone receptor-like factors
**2.2 Class: diverse Cys4 zinc fingers
***2.2.1 Family: GATA-Factors
**2.3 Class: Cys2His2 zinc finger domain
***2.3.1 Family: Ubiquitous factors, includes
***2.3.2 Family: Developmental / cell cycle regulators; includes
***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
**3.1 Class: Homeo domain
***3.1.1 Family: Homeo domain only; includes
***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
***3.3.2 Family: Tissue-specific regulators
***3.3.3 Family: Cell-cycle controlling factors
***3.3.0 Family: Other regulators
Heat Shock Factors
***3.4.1 Family: HSF
**3.5 Class: Tryptophan clusters
***3.5.1 Family: Myb
***3.5.2 Family: Ets-type
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 region)
***4.1.1 Family: Rel/ankyrin; NF-kappaB
***4.1.2 Family: ankyrin only
***4.1.3 Family: NF-AT (Nuclear Factor of Activated T-cells) (
NFATC1, NFATC2, NFATC3)
**4.2 Class: STAT
***4.2.1 Family: STAT
**4.3 Class: p53
**4.4 Class: MADS box
***4.4.1 Family: Regulators of differentiation; includes (
****4.4.2 Family: Responders to external signals, SRF (
serum response factor) (gene|SRF)
**4.5 Class: beta-Barrel alpha-helix transcription factors
TATA binding proteins
***4.6.1 Family: TBP
SOX genes, SRY
***4.7.2 Family: TCF-1 (TCF1)
***4.7.3 Family: HMG2-related, SSRP1
***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) (
***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: ARF
****0.5.3.2 Family: ABI
****0.5.3.3 Family: RAV
Inhibitor of DNA-binding protein
Nuclear receptor, a class of ligand activated transcription factors
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