Transcription factor

In

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.^[14]

There are approximately 2800 proteins in the human genome that contain DNA-binding domains, and 1600 of these are presumed to function as transcription factors,^[3] though other studies indicate it to be a smaller number.^[15] 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.^[13]

Mechanism

Transcription factors bind to either

• stabilize or block the binding of RNA polymerase to DNA^[citation needed]
• 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:^[17]
  • 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
  corepressor proteins to the transcription factor DNA complex^[18]

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.^{[citation needed]}

Development

Many transcription factors in

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.^[27] 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.^[28]

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

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.^[39]

Nuclear localization

In

• 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).
• phosphorylation^[41][42] – 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^{[citation needed]}

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 pioneer 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.^[43] 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.^[44] Pairs of transcription factors and other proteins can play antagonistic roles (activator versus repressor) in the regulation of the same gene.^{[citation needed]}

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.^[45] 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.^[46]

Interaction with methylated cytosine

Transcription factors and methylated cytosines in DNA both have major roles in regulating gene expression. (Methylation of cytosine in DNA primarily occurs where cytosine is followed by guanine in the 5' to 3' DNA sequence, a CpG site.) Methylation of CpG sites in a promoter region of a gene usually represses gene transcription,^[47] while methylation of CpGs in the body of a gene increases expression.^[48] TET enzymes play a central role in demethylation of methylated cytosines. Demethylation of CpGs in a gene promoter by TET enzyme activity increases transcription of the gene.^[49]

The DNA binding sites of 519 transcription factors were evaluated.^[50] Of these, 169 transcription factors (33%) did not have CpG dinucleotides in their binding sites, and 33 transcription factors (6%) could bind to a CpG-containing motif but did not display a preference for a binding site with either a methylated or unmethylated CpG. There were 117 transcription factors (23%) that were inhibited from binding to their binding sequence if it contained a methylated CpG site, 175 transcription factors (34%) that had enhanced binding if their binding sequence had a methylated CpG site, and 25 transcription factors (5%) were either inhibited or had enhanced binding depending on where in the binding sequence the methylated CpG was located.^{[citation needed]}

TET enzymes do not specifically bind to methylcytosine except when recruited (see

Transcription factors are modular in structure and contain the following

• response elements
  .
• TAD, not to be confused with topologically associating domain (TAD).^[53]
• An optional signal-sensing domain (SSD) (e.g., a ligand-binding domain), which senses external signals and, in response, transmits these signals to the rest of the transcription complex, resulting in up- or down-regulation of gene expression. Also, the DBD and signal-sensing domains may reside on separate proteins that associate within the transcription complex to regulate gene expression.

DNA-binding domain

Main article: 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	InterPro	Pfam	SCOP
basic helix-loop-helix[54]	InterPro: IPR001092	Pfam PF00010	SCOP 47460
basic-leucine zipper (bZIP)[55]	InterPro: IPR004827	Pfam PF00170	SCOP 57959
C-terminal effector domain of the bipartite response regulators	InterPro: IPR001789	Pfam PF00072	SCOP 46894
AP2/ERF/GCC box	InterPro: IPR001471	Pfam PF00847	SCOP 54176
helix-turn-helix[56]
homeodomain proteins, which are encoded by homeobox genes, are transcription factors. Homeodomain proteins play critical roles in the regulation of development.[57][58]	InterPro: IPR009057	Pfam PF00046	SCOP 46689
lambda repressor -like	InterPro: IPR010982		SCOP 47413
srf-like (serum response factor)	InterPro: IPR002100	Pfam PF00319	SCOP 55455
paired box[59]
winged helix	InterPro: IPR013196	Pfam PF08279	SCOP 46785
zinc fingers[60]
* multi-domain Cys2His2 zinc fingers[61]	InterPro: IPR007087	Pfam PF00096	SCOP 57667
* Zn2/Cys6			SCOP 57701
* Zn2/Cys8 nuclear receptor zinc finger	InterPro: IPR001628	Pfam PF00105	SCOP 57716

Response elements

The DNA sequence that a transcription factor binds to is called a

transcription factor-binding site or response element.^[62]

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.^{[citation needed]}

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.^{[citation needed]}

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.^[63]

Many transcription factors are either

NF-kappaB and AP-1 families, (2) the STAT family and (3) the steroid receptors.^[64]

Below are a few of the better-studied examples:

Condition	Description	Locus
Rett syndrome	Mutations in the MECP2 transcription factor are associated with Rett syndrome, a neurodevelopmental disorder.[65][66]	Xq28
Diabetes	A rare form of insulin promoter factor-1 (IPF1/Pdx1).[68]	multiple
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.[69]	7q31
Autoimmune diseases	Mutations in the IPEX.[70]	Xp11.23-q13.3
Li-Fraumeni syndrome	Caused by mutations in the tumor suppressor p53.[71]	17p13.1
Breast cancer	The STAT family is relevant to breast cancer.[72]	multiple
Multiple cancers	The HOX family are involved in a variety of cancers.[73]	multiple
Osteoarthritis	Mutation or reduced activity of SOX9[74]

Potential drug targets

See also: Therapeutic gene modulation

Approximately 10% of currently prescribed drugs directly target the

signaling cascades. It might be possible to directly target other less-explored transcription factors such as NF-κB with drugs.^{[77][78][79][80]} 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 Pax2^[81][82] and the notch pathway.^[83]

Role in evolution

Further information: Evolutionary developmental biology

Gene duplications have played a crucial role in the

phylogenetic hypotheses, and the role of transcription factors in the evolution of all species.^[84][85]

Role in biocontrol activity

The transcription factors have a role in

biocontrol activity. The resistant to oxidative stress and alkaline pH sensing were contributed from the transcription factor Yap1 and Rim101 of the Papiliotrema terrestris LS28 as molecular tools revealed an understanding of the genetic mechanisms underlying the biocontrol activity which supports disease management programs based on biological and integrated control.^[86]

Analysis

There are different technologies available to analyze transcription factors. On the

antibodies. The sample is detected on a western blot. By using electrophoretic mobility shift assay (EMSA),^[88] 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.^{[citation needed}

]

The most commonly used method for identifying transcription factor binding sites is

ChIP-seq) to determine transcription factor binding sites. If no antibody is available for the protein of interest, DamID may be a convenient alternative.^[90]

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:

• TFIIH. They are ubiquitous and interact with the core promoter region surrounding the transcription start site(s) of all class II genes.^[91]
• 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.^[92]

Examples of specific transcription factors[92]
Factor	Structural type	Recognition sequence	Binds as
SP1	Zinc finger	3'	Monomer
AP-1	Basic zipper	5'-TGA(G/C)TCA-3'	Dimer
C/EBP	Basic zipper	5'-ATTGCGCAAT-3'	Dimer
Heat shock factor	Basic zipper	5'-XGAAX-3'	Trimer
ATF/CREB	Basic zipper	5'-TGACGTCA-3'	Dimer
c-Myc	Basic helix-loop-helix	5'-CACGTG-3'	Dimer
Oct-1	Helix-turn-helix	5'-ATGCAAAT-3'	Monomer
NF-1	Novel	5'-TTGGCXXXXXGCCAA-3'	Dimer
(G/C) = G or C X = A, T, G or C

Functional

Transcription factors have been classified according to their regulatory function:^[13]

• I. constitutively active – present in all cells at all times –
  CCAAT
• II. conditionally active – requires activation
  • II.A developmental (cell specific) – expression is tightly controlled, but, once expressed, require no additional activation –
    Hox, Winged Helix
  • II.B signal-dependent – requires external signal for activation
    • II.B.1 extracellular ligand (
      paracrine)-dependent – nuclear receptors
    • II.B.2 intracellular ligand (
      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 –
        AP-1, Mef2
      • II.B.3.b latent cytoplasmic factors – inactive form reside in the cytoplasm, but, when activated, are translocated into the nucleus –
        Notch, TUBBY, NFAT

Structural

Transcription factors are often classified based on the

tertiary structure of their DNA-binding domains:^{[93][12][94][11]}

• 1 Superclass: Basic Domains
  • 1.1 Class:
    bZIP
    )
    • 1.1.1 Family:
      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
      )
    • 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
  • 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
      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 ( 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: NFAT (Nuclear Factor of Activated T-cells) (NFATC1, NFATC2, NFATC3)
  • 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) (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:
      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: ARF
      • 0.5.3.2 Family: ABI
      • 0.5.3.3 Family: RAV

Transcription factor databases

There are numerous databases cataloging information about transcription factors, but their scope and utility vary dramatically. Some may contain only information about the actual proteins, some about their binding sites, or about their target genes. Examples include the following:

• footprintDB-- a metadatabase of multiple databases, including JASPAR and others
• JASPAR: database of transcription factor binding sites for eukaryotes
• PlantTFD: Plant transcription factor database^[95]
• TcoF-DB: Database of transcription co-factors and transcription factor interactions^[96]
• TFcheckpoint: database of human, mouse and rat TF candidates
• transcriptionfactor.org (now commercial, selling reagents)
• MethMotif.org: An integrative cell-specific database of transcription factor binding motifs coupled with DNA methylation profiles. ^[97]

See also

• Cdx protein family
• DNA-binding protein
• Inhibitor of DNA-binding protein
• Mapper(2)
• Nuclear receptor, a class of ligand activated transcription factors
• Open Regulatory Annotation Database
• Phylogenetic footprinting
• TRANSFAC database
• YeTFaSCo

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Further reading

• Carretero-Paulet, Lorenzo; Galstyan, Anahit; Roig-Villanova, Irma; Martínez-García, Jaime F.; Bilbao-Castro, Jose R. «Genome-Wide Classification and Evolutionary Analysis of the bHLH Family of Transcription Factors in Arabidopsis, Poplar, Rice, Moss, and Algae». Plant Physiology, 153, 3, 2010-07, pàg. 1398–1412.
  ISSN 0032-0889
• Jin J, He K, Tang X, Li Z, Lv L, Zhao Y, et al. (2015). "An Arabidopsis Transcriptional Regulatory Map Reveals Distinct Functional and Evolutionary Features of Novel Transcription Factors". Molecular Biology and Evolution. 32 (7): 1767–73.
  PMID 25750178
  .

External links

• Transcription+Factors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Transcription factor database Archived 4 December 2008 at the Wayback Machine