(Redirected from Transcription factors)
In the field of
molecular biology, a 'transcription 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.
[1][2]
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.
[3][4]
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 ()
★ Zn
2/Cys
6 ()
★
winged helix () ()
★ Zn
2/Cys
8 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 Cys
2His
2 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.
[5] (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.
Structure
Transcription factors are modular in structure and contain the following
domains:
1
★ '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').
[6]
★ 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.
Mechanism of action
Transcription factors may be activated (or deactivated) through their 'signal sensing domain' by a number of mechanisms including:
★
ligand binding (see for example
nuclear receptors)
★
phosphorylation[7]
★ interactions with other transcription factors (''e.g.'', homo- or hetero-
dimerization) and/or
coregulatory proteins
The resulting activated transcription factors through their DBD bind to specific sequences of DNA upstream or downstream to the gene they regulate and then either enhance or repress transcription of these genes by assisting or blocking RNA polymerase binding respectively. A cluster of transcription factors is the
preinitiation complex (PIC) that recruits and activates
RNA polymerase. Conversely, repressor transcription factors inhibit transcription by blocking the attachment of activator proteins.
The regulation of transcription is a highly complex process as it is dependent upon a number of factors including which transcription factors and other coregulatory proteins are present within a particular cell as well as the local 3-dimensional structure of the gene (
chromatin).
Initial models, based on ''in vitro'' experiments suggested that the assembly of transcription factors dictated by the DNA sequence. It is, however, becoming increasingly obvious that the events leading to activation of transcription are dependent on a large number of factors and are highly intertwined. Furthermore
epigenetic information present on DNA appears to play an important role in transcriptional activation.
Classes
Mechanistic
There are three mechanistic classes of transcription factors:
[8]
★
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.
[9]
★ '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
Alternatively transcription factors have been classified according to their regulatory function:
5
★ 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' - inacitve 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.
[10]
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.
[11] 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.
5
Classification of Transcription Factors
Transcription factors are often classified based on the similarity of their DNA binding domains:
[12]15[13]
★ 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
References
1. Transcription factors: an overview, Latchman DS, , , Int. J. Biochem. Cell Biol., 1997
2. Too many transcription factors: positive and negative interactions, Karin M, , , New Biol., 1990
3. The role of general initiation factors in transcription by RNA polymerase II, Roeder RG, , , Trends Biochem. Sci., 1996
4. RNA polymerase II transcription initiation: a structural view, Nikolov DB, Burley SK, , , Proc. Natl. Acad. Sci. U.S.A., 1997
5. Signal transduction and the control of gene expression, Brivanlou AH, Darnell JE, , , Science, 2002
6. Activation functions 1 and 2 of nuclear receptors: molecular strategies for transcriptional activation, Wärnmark A, Treuter E, Wright AP, Gustafsson J-Å, , , Mol. Endocrinol., 2003
7. Steroid Receptor Phosphorylation: A Key Modulator of Multiple Receptor Functions, Weigel NL, Moore NL, , , , 2007
8. ISCID Encyclopedia transcription factor definition
9. The general transcription factors of RNA polymerase II, Orphanides G, Lagrange T, Reinberg D, , , Genes Dev., 1996
10. Scaling laws in the functional content of genomes, van Nimwegen E, , , Trends Genet., 2003
11. Structure and evolution of transcriptional regulatory networks, Babu MM, Luscombe NM, Aravind L, Gerstein M, Teichmann SA, , , Curr. Opin. Struct. Biol., 2004
12. Systematic DNA-binding domain classification of transcription factors, Stegmaier P, Kel AE, Wingender E, , , Genome informatics. International Conference on Genome Informatics, 2004
13. TRANSFAC® database
14. Developmental Biology, Singer, Susan R.; Gilbert, Scott F., , , Sinauer Associates, 2006,
15. TRANSFAC® and its module TRANSCompel:® transcriptional gene regulation in eukaryotes, 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, , , Nucleic Acids Res., 2006
See also
★
Brachyury
★
DNA-binding protein
★
E2F
★
MCEF
★
Nanog (transcription factor)
★
Nuclear receptor, a class of ligand activated transcription factors
★
Oct-4
★
Pax genes
★
Sox2
External links
★
Transcription factors: DevBio on-line supplementary material to ''Developmental Biology'' by Scott F. Gilbert[14]
★
A classification of transcription factors based on their DNA-binding domains[15]
★
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