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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 sequences of DNA and thereby controls the transfer (or transcription) of genetic information from DNA to RNA. 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.

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. 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.

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 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.

Function

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

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:

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.

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. 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 this 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).
phosphorylation – 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 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

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 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:

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

Response elements

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

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 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) which bind to two or more adjacent sequences of DNA.

Clinical significance

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.

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 in their DNA binding domains.

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 allclass 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