Editing Transcription factor (section)

== 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. They are also classified by 3D structure of their DBD and the way it contacts DNA.<ref name=":0">{{cite journal | vauthors = Wingender E, Schoeps T, Haubrock M, Dönitz J | title = TFClass: a classification of human transcription factors and their rodent orthologs | journal = Nucleic Acids Research | volume = 43 | issue = Database issue | pages = D97-102 | date = January 2015 | pmid = 25361979 | pmc = 4383905 | doi = 10.1093/nar/gku1064 }}</ref><ref name=":1">{{cite journal | vauthors = Blanc-Mathieu R, Dumas R, Turchi L, Lucas J, Parcy F | title = Plant-TFClass: a structural classification for plant transcription factors | journal = Trends in Plant Science | volume = 29 | issue = 1 | pages = 40–51 | date = January 2024 | pmid = 37482504 | doi = 10.1016/j.tplants.2023.06.023 | bibcode = 2024TPS....29...40B }}</ref>

=== Mechanistic ===

There are two mechanistic classes of transcription factors:
* [[General transcription factor]]s are involved in the formation of a [[Transcription preinitiation complex|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 gene]]s.<ref name="pmidc">{{Cite journal |vauthors=Orphanides G, Lagrange T, Reinberg D |date=November 1996 |title=The general transcription factors of RNA polymerase II |journal=Genes & Development |volume=10 |issue=21 |pages=2657–83 |doi=10.1101/gad.10.21.2657 |pmid=8946909 |doi-access=free}}</ref>
* '''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 sequence]]s are present in the proximity of the gene.<ref name="boron125-126">{{Cite book |title=Medical Physiology: A Cellular And Molecular Approaoch |vauthors=Boron WF |publisher=Elsevier/Saunders |year=2003 |isbn=1-4160-2328-3 |pages=125–126}}</ref>

{|class="wikitable"
!colspan=4| Examples of specific transcription factors<ref name="boron125-126" />
|-
! Factor !! Structural type !! [[Recognition sequence]] !! Binds as
|-
! [[Sp1 transcription factor|SP1]]
| [[Zinc finger]] || [[five prime end|5']]-GGGCGG-[[three prime end|3']] || Monomer
|-
! [[AP-1 transcription factor|AP-1]]
| [[Basic zipper]] || 5'-TGA(G/C)TCA-3' || Dimer
|-
! [[Ccaat-enhancer-binding proteins|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
|-
! [[Myc|c-Myc]]
| [[Basic helix-loop-helix]]
| 5'-CACGTG-3' || Dimer
|-
! [[POU2F1|Oct-1]]
| [[Helix-turn-helix]] || 5'-ATGCAAAT-3' || Monomer
|-
! [[Nuclear factor 1|NF-1]]
| Novel || 5'-TTGGCXXXXXGCCAA-3' || Dimer
|-
|colspan=4| (G/C) = G or C <br /> X = [[adenine|A]], [[thymine|T]], [[guanine|G]] or [[cytosine|C]]
|}

=== Functional ===

Transcription factors have been classified according to their regulatory function:<ref name="pmid11823631" />
* I. '''Constitutive''' – present in all cells at all times, constantly active, all being [[Activator (genetics)|activators]]. Very likely playing an important facilitating role in the transcription of many chromosomal genes, possibly in genes that seem to be always transcribed (e.g., structural proteins like tubulin and actin, and ubiquitous metabolic enzymes such as glyceraldehyde phosphate dehydrogenase (GAPDH)). E.g.: [[general transcription factor]]s, [[Sp1 transcription factor|Sp1]], [[Nuclear factor 1|NF1]], [[Ccaat-enhancer-binding proteins|CCAAT]]
* II. '''Regulatory (conditionally active)''' – require activation.
** II.A '''Developmental''' '''(cell-type specific)''' – beginning in a fertilized egg. Once expressed, require no additional activation. E.g.:[[GATA transcription factor|GATA]], [[hepatocyte nuclear factors|HNF]], [[PIT-1]], [[MyoD]], [[Myf5]], [[Hox (gene)|Hox]], [[winged-helix transcription factors|Winged Helix]]
** II.B '''Signal-dependent''' – may be either developmentally restricted in their expression or present in most or all cells, but all are inactive (or minimally active) until cells containing such proteins are exposed to the appropriate intra- or extracellular signal.
*** II.B.1 '''Extracellular ligand ([[endocrine system|endocrine]] or [[paracrine signalling|paracrine]])-dependent''' – [[nuclear receptor]]s.
*** II.B.2 '''Intracellular ligand ([[autocrine signalling|autocrine]])-dependent''' – activated by small intracellular molecules. E.g.: [[Sterol regulatory element binding protein|SREBP]], [[p53]], orphan nuclear receptors.
*** II.B.3 '''Cell surface receptor-ligand interaction-dependent''' – activated by second messenger signaling cascades.
**** II.B.3.a Constitutive nuclear factors activated by serine phosphorylation – residing within the nucleus. The serine phosphorylation enzymes can be activated by two main routes:
***** [[G protein-coupled receptor|G protein-coupled receptors]] upon ligand binding increase intracellular levels of [[Second messenger system|second messengers]] ([[Cyclic adenosine monophosphate|cAMP]], [[Inositol trisphosphate|IP<sub>3</sub>]], [[Diglyceride|DAG]], calcium) which, in turn, activate protein [[serine-threonine kinase]] enzymes (such as [[Protein kinase A|PKA]], [[Protein kinase C|PKC]]).
***** [[Receptor tyrosine kinase|Receptor tyrosine kinases]] upon ligand binding trigger other pathways that finally terminate in serine phosphorylation of the abundant resident nuclear transcription factors.
***** Examples include: [[CREB]], [[AP-1 (transcription factor)|AP-1]], [[Mef2]]
**** II.B.3.b '''Latent cytoplasmic factors''' – residing in the cytoplasm when inactive. Structurally and chemically very diverse group, and so are their activation pathways. E.g.: [[STAT protein|STAT]], [[R-SMAD]], [[NF-κB]], [[Notch signaling|Notch]], [[Tubby protein|TUBBY]], [[NFAT]]

=== Structural ===

Transcription factors are often classified based on the [[Sequence homology#Homology of sequences in genetics|sequence similarity]] and hence the [[tertiary structure]] of their DNA-binding domains.<ref name="pmid15706513">{{Cite journal |vauthors=Stegmaier P, Kel AE, Wingender E |year=2004 |title=Systematic DNA-binding domain classification of transcription factors |url=http://www.jsbi.org/journal/GIW04/GIW04F028.html |url-status=dead |journal=Genome Informatics. International Conference on Genome Informatics |volume=15 |issue=2 |pages=276–86 |pmid=15706513 |archive-url=https://web.archive.org/web/20130619202726/http://www.jsbi.org/journal/GIW04/GIW04F028.html |archive-date=19 June 2013}}</ref><ref name="Matys_2006">{{Cite journal |vauthors=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 |date=January 2006 |title=TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes |journal=Nucleic Acids Research |volume=34 |issue=Database issue |pages=D108-10 |doi=10.1093/nar/gkj143 |pmc=1347505 |pmid=16381825}}</ref><ref>{{Cite web |title=TRANSFAC database |url=http://www.gene-regulation.com/pub/databases/transfac/cl.html |access-date=5 August 2007}}</ref><ref name="Jin_2014" /> The following classification is based of the 3D structure of their [[DNA-binding domain|DBD]] and the way it contacts DNA. It was first developed for Human TF and later extended to rodents <ref name=":0" /> and also to plants.<ref name=":1" /> 
* 1 Superclass: Basic Domains
** 1.1 Class: [[Leucine zipper]] factors ([[bZIP]])
*** 1.1.1 Family: [[AP-1 (transcription factor)|AP-1]](-like) components; includes ([[c-Fos]]/[[c-Jun]])
*** 1.1.2 Family: [[CREB]]
*** 1.1.3 Family: [[Ccaat-enhancer-binding proteins|C/EBP]]-like factors
*** 1.1.4 Family: bZIP / [[PAR (transcription factor)|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 ([[basic helix-loop-helix leucine zipper transcription factors|bHLH-ZIP]])
*** 1.3.1 Family: Ubiquitous bHLH-ZIP factors; includes USF  ([[USF1]], [[USF2]]); SREBP ([[Sterol regulatory element binding protein|SREBP]])
*** 1.3.2 Family: Cell-cycle controlling factors; includes [[Myc|c-Myc]]
** 1.4 Class: NF-1
*** 1.4.1 Family: NF-1  ([[NFIA|A]], [[NFIB (gene)|B]], [[NFIC (gene)|C]], [[NFIX|X]])
** 1.5 Class: RF-X
*** 1.5.1 Family: RF-X ([[RFX1|1]], [[RFX2|2]], [[RFX3|3]], [[RFX4|4]], [[RFX5|5]], [[RFXANK|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 receptor]]s
*** 2.1.2 Family: [[Thyroid hormone receptor]]-like factors
** 2.2 Class: diverse Cys4 zinc fingers
*** 2.2.1 Family: [[GATA transcription factor|GATA-Factors]]
** 2.3 Class: Cys2His2 zinc finger domain
*** 2.3.1 Family: Ubiquitous factors, includes [[TFIIIA]], [[Sp1 transcription factor|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: [[Homeobox|Homeo domain]]
*** 3.1.1 Family: Homeo domain only; includes [[Ubx]]
*** 3.1.2 Family: [[POU family|POU domain]] factors; includes [[Octamer transcription factor|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: [[FOX proteins|Fork head]] / [[Winged-helix transcription factors|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 Factor]]s
*** 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 domain|Rel homology region]])
*** 4.1.1 Family: Rel/[[Ankyrin repeat|ankyrin]]; [[NF-κB|NF-kappaB]]
*** 4.1.2 Family: ankyrin only
*** 4.1.3 Family: [[NFAT]] ('''N'''uclear '''F'''actor of '''A'''ctivated '''T'''-cells) ([[NFATC1]], [[NFATC2]], [[NFATC3]])
** 4.2 Class: STAT
*** 4.2.1 Family: [[STAT protein|STAT]]
** 4.3 Class: p53
*** 4.3.1 Family: [[p53]]
** 4.4 Class: [[MADS-box|MADS box]]
*** 4.4.1 Family: Regulators of differentiation; includes ([[Mef2]])
*** 4.4.2 Family: Responders to external signals, SRF ([[serum response factor]])  ({{gene|SRF}})
*** 4.4.3 Family: Metabolic regulators (ARG80)
** 4.5 Class: beta-Barrel alpha-helix transcription factors
** 4.6 Class: [[TATA binding protein]]s
*** 4.6.1 Family: TBP
** 4.7 Class: [[HMG-box]]
*** 4.7.1 Family: [[SOX genes]], [[SRY]]
*** 4.7.2 Family: TCF-1 ([[HNF1A|TCF1]])
*** 4.7.3 Family: HMG2-related, [[Structure specific recognition protein 1|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: [[Apetala 2|AP2]]
*** 0.5.2 Family: EREBP
*** 0.5.3 Superfamily: [[B3 DNA-binding domain|AP2/B3]]
**** 0.5.3.1 Family: ARF
**** 0.5.3.2 Family: ABI
**** 0.5.3.3 Family: RAV