User:Forluvoft/sandbox/Transcription factor

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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]

Transcription factor glossary
  • gene expression – the process by which information from a gene is used in the synthesis of a functional gene product such as a protein
  • transcription – the process of making messenger RNA (mRNA) from a DNA template by RNA polymerase
  • transcription factor – a protein that binds to DNA and regulates gene expression by promoting or suppressing transcription
  • transcriptional regulation – controlling the rate of gene transcription for example by helping or hindering RNA polymerase binding to DNA
  • upregulation, activation, or promotion – increase the rate of gene transcription
  • downregulation, repression, or suppression – decrease the rate of gene transcription
  • coactivator – a protein (or a small molecule) that works with transcription factors to increase the rate of gene transcription
  • corepressor – a protein (or a small molecule) that works with transcription factors to decrease the rate of gene transcription
  • response element – a specific sequence of DNA that a transcription factor binds to



Mechanism of action[edit]

In order to regulate transcription, a transcription factor binds DNA and helps recruit other transcription factors, coactivators/corepressors, or chromatin remodeling complexes. In eukaryotes, this paves the way for the eventual recruitment of the Mediator complex, basal transcription factors, and eventually RNA polymerase which transcribes the gene sequence into an RNA copy.

Transcription factor binding to promoters (sequences just upstream of the transcription start site) is the most studied. This is the site where the preinitiation complex (PIC) assembles and RNA polymerase is recruited. It is also the easiest DNA regulatory sequence to find because of its location next to the transcription start site and all genes are generally assumed to have promoters. Despite this, transcription factors also have an important role in binding to more distant DNA regulatory regions such as enhancers and locus control regions. These regulatory sequences can be thousands of base pairs away from the gene they regulate, making their identification difficult. Recent advances in comparative genomics and chromatin immunoprecipitation, however, is likely to make the role of transcription factors in long-range gene regulation better understood.

binding to silencers? repression vs activation?

Structure[edit]

Schematic diagram of the amino acid sequence (amino terminus to the left and carboxylic acid terminus to the right) of a prototypical transcription factor which contains (1) a DNA-binding domain (DBD), (2) signal sensing domain (SSD), and a transactivation domain (TAD). The order of placement and the number of domains may differ in various types of transcription factors. In addition, the transactivation and signal sensing functions are frequently contained within the same domain.

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).[5]
  • 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[edit]

The portion (domain) of the transcription factor that binds DNA is called its DNA binding domain.


Transcription factor binding sites/response elements[edit]

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.


Classes[edit]

Mechanistic[edit]

There are three mechanistic classes of transcription factors:[6]

  • 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.[7]
  • 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[edit]

Alternatively transcription factors have been classified according to their regulatory function:[8]

  • 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[edit]

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.[9]

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.[10] 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.[8]


Classification of transcription factors[edit]

Transcription factors are often classified based on the similarity of their DNA binding domains:[11][12][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 (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
    • 1.6 Class: bHSH
  • 2 Superclass: Zinc-coordinating DNA-binding domains
    • 2.1 Class: Cys4 zinc finger of nuclear receptor type
    • 2.2 Class: diverse Cys4 zinc fingers
    • 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
    • 3.6 Class: TEA domain
      • 3.6.1 Family: TEA (TEAD1)
  • 4 Superclass: beta-Scaffold Factors with Minor Groove Contacts
    • 4.1 Class: RHR (Rel homology region)
    • 4.2 Class: 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)
    • 4.5 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 (TCF1)
      • 4.7.3 Family: HMG2-related, SSRP1 (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) (HMGA1)
      • 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[edit]

  1. ^ a b Latchman DS (1997). "Transcription factors: an overview". Int. J. Biochem. Cell Biol. 29 (12): 1305–12. doi:10.1016/S1357-2725(97)00085-X. PMID 9570129.
  2. ^ Karin M (1990). "Too many transcription factors: positive and negative interactions". New Biol. 2 (2): 126–31. PMID 2128034.
  3. ^ Roeder RG (1996). "The role of general initiation factors in transcription by RNA polymerase II". Trends Biochem. Sci. 21 (9): 327–35. doi:10.1016/0968-0004(96)10050-5. PMID 8870495.
  4. ^ Nikolov DB, Burley SK (1997). "RNA polymerase II transcription initiation: a structural view". Proc. Natl. Acad. Sci. U.S.A. 94 (1): 15–22. doi:10.1073/pnas.94.1.15. PMID 8990153.
  5. ^ Wärnmark A, Treuter E, Wright AP, Gustafsson J-Å (2003). "Activation functions 1 and 2 of nuclear receptors: molecular strategies for transcriptional activation". Mol. Endocrinol. 17 (10): 1901–9. doi:10.1210/me.2002-0384. PMID 12893880.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ "ISCID Encyclopedia transcription factor definition". Retrieved 2007-08-02.
  7. ^ Orphanides G, Lagrange T, Reinberg D (1996). "The general transcription factors of RNA polymerase II". Genes Dev. 10 (21): 2657–83. doi:10.1101/gad.10.21.2657. PMID 8946909.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ a b Brivanlou AH, Darnell JE (2002). "Signal transduction and the control of gene expression". Science. 295 (5556): 813–8. doi:10.1126/science.1066355. PMID 11823631.
  9. ^ van Nimwegen E (2003). "Scaling laws in the functional content of genomes". Trends Genet. 19 (9): 479–84. doi:10.1016/S0168-9525(03)00203-8. PMID 12957540.
  10. ^ Babu MM, Luscombe NM, Aravind L, Gerstein M, Teichmann SA (2004). "Structure and evolution of transcriptional regulatory networks". Curr. Opin. Struct. Biol. 14 (3): 283–91. doi:10.1016/j.sbi.2004.05.004. PMID 15193307.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ Stegmaier P, Kel AE, Wingender E (2004). "Systematic DNA-binding domain classification of transcription factors". Genome informatics. International Conference on Genome Informatics. 15 (2): 276–86. PMID 15706513.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ Cite error: The named reference pmid16381825 was invoked but never defined (see the help page).
  13. ^ "TRANSFAC® database". Retrieved 2007-08-05.

See also[edit]

External links[edit]

  1. ^ Singer, Susan R.; Gilbert, Scott F. (2006). Developmental Biology. Sunderland, Mass: Sinauer Associates. ISBN 0-87893-250-X.{{cite book}}: CS1 maint: multiple names: authors list (link)
  2. ^ 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 (2006). "TRANSFAC® and its module TRANSCompel:® transcriptional gene regulation in eukaryotes". Nucleic Acids Res. 34 (Database issue): D108-10. doi:10.1093/nar/gkj143. PMID 16381825.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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