Transcription factor

In the field of molecular biology, a transcription factor (sometimes called a sequence-specific DNA binding factor) is a protein that binds to specific parts of DNA using DNA binding domains and is part of the system that controls the transfer (or transcription) of genetic information from DNA to RNA.

Transcription factors perform this function alone, or by using other proteins in a complex, by increasing (as an activator), or preventing (as a repressor) the presence of RNA polymerase, a protein which transcribes genetic information.

Biological roles
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 In eukaryotes, an important class of transcription factors called general transcription factors (GTFs) are necessary for transcription to occur.  Many of these GTFs don't actually bind DNA but 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.


 * Development Many transcription factors in multicellular organisms are involved in development.  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 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.  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.


 * 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.  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.


 * 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 lipid levels 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 Myc oncogene, which has important roles in cell growth and apoptosis.

Regulation of transcription factor activity
It is common in biology for important processes to have multiple layers of regulation and control. This is just as true with transcription: not only do rates of transcription regulate the amounts of gene products (RNA and protein) available to the cell, but the process of transcription itself is regulated. Below is a brief synopsis of some of the ways that the activity of transcription factors can be regulated:


 * Transcription factor 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.  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.


 * Localization to the nucleus 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.  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 via chemical modifications or 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.  Another way that a transcription factor can be activated is by chemical modification of the transcription factor itself.  For example, many transcription factors such as STAT proteins must be phosphorylated before they can bind DNA.


 * 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 chromatin fibers.  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 needed for a complex 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 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.



Structure
Transcription factors are modular in structure and contain the following domains:
 * DNA-binding domain (DBD) which attach to specific sequences of DNA (enhancer or promoter sequences) 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).
 * 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 domains
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:


 * lambda repressor-like
 * C-terminal effector domain of the bipartite response regulators
 * srf-like (serum response factor)
 * basic-helix-loop-helix
 * GCC box
 * Zn2/Cys6
 * winged helix
 * Zn2/Cys8 nuclear receptor zinc finger
 * homeodomain proteins - bind to homeobox DNA sequences which in turn encode other transcription factors. Homeodomain proteins play critical roles in the regulation of development.
 * multi-domain Cys2His2 zinc fingers
 * basic-leucine zipper (bZIP)

There are other proteins that play crucial roles in the regulation of transcription, that aren't classified as transcription factors because they lack DNA binding domains. (for example coactivators, chromatin remodelers, histone acetylases, deacetylases, kinases, and methylases).

Transcription factor binding sites/response elements
The DNA sequence that a transcription factor binds to is called a transcription factor binding site or response element.

Chemically, transcription factors usually interact with their binding sites using a combination of hydrogen bonds 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 the sequences don't tend to be that long, potential transcription factor binding sites can occur just by chance if the DNA sequence is long enough. It is unlikely, however, that a transcription factor binds 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.

Mechanistic
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.
 * 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.

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-dependent - nuclear receptors
 * 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

Roles and 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.

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. 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 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 and human disease
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 MECP2 transcription factor are associated with Rett syndrome, a neurodevelopmental disorder.


 * Diabetes A rare form of diabetes called 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 FOXP2 transcription 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 FOXP3 transcription factor cause a rare form of autoimmune disease called 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 syndrome is caused by mutations in the tumor suppressor p53.

Classification of transcription factors
Transcription factors are often classified based on the similarity of their DNA binding domains:


 * 1 Superclass: Basic Domains (Basic-helix-loop-helix)
 * 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 ; SREBP (SREBP)
 * 1.3.2 Family: Cell-cycle controlling factors; includes c-Myc
 * 1.4 Class: NF-1
 * 1.4.1 Family: NF-1
 * 1.5 Class: RF-X
 * 1.5.1 Family: RF-X
 * 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 receptors
 * 2.1.2 Family: 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 TFIIIA, 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: 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
 * 3.5.1 Family: Myb
 * 3.5.2 Family: Ets-type
 * 3.5.3 Family: Interferon regulatory factors
 * 3.6 Class: TEA domain
 * 3.6.1 Family: TEA


 * 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
 * 4.2 Class: STAT
 * 4.2.1 Family: 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)
 * 4.5 Class: beta-Barrel alpha-helix transcription factors
 * 4.6 Class: TATA binding proteins
 * 4.6.1 Family: TBP
 * 4.7.1 Family: SOX genes, SRY
 * 4.7.2 Family: TCF-1
 * 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: AP-2/EREBP-related factors