Inmolecular biology, atranscription factor (TF) (orsequence-specific DNA-binding factor) is aprotein that controls the rate oftranscription ofgenetic information fromDNA tomessenger RNA, by binding to a specificDNA sequence.[1][2] The function of TFs is to regulate—turn on and off—genes in order to make sure that they areexpressed in the desiredcells at the right time and in the right amount throughout the life of the cell and the organism. Groups of TFs function in a coordinated fashion to directcell division,cell growth, andcell death throughout life;cell migration and organization (body plan) during embryonic development; and intermittently in response to signals from outside the cell, such as ahormone. There are approximately 1600 TFs in thehuman genome, where half of them areC2H2 zinc fingers.[3][4][5][6] Transcription factors are members of theproteome as well asregulome.
TFs work alone or with other proteins in a complex, by promoting (as anactivator), or blocking (as arepressor) the recruitment ofRNA polymerase (the enzyme that performs thetranscription of genetic information from DNA to RNA) to specific genes.[7][8][9]
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.[15]
There are approximately 2800 proteins in thehuman genome that contain DNA-binding domains, and 1600 of these are presumed to function as transcription factors,[3] where half of them (~800) are C2H2 zinc finger proteins.[6] 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 duringdevelopment.[14]
Transcription factors bind to eitherenhancer orpromoter regions of DNA adjacent to the genes that they regulate based on recognizing specific DNA motifs. Depending on the transcription factor, the transcription of the adjacent gene is eitherup- or down-regulated. Transcription factors use a variety of mechanisms for the regulation of gene expression.[16] These mechanisms include:
stabilize or block the binding of RNA polymerase to DNA[citation needed]
catalyze theacetylation or deacetylation ofhistone 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 – acetylateshistone proteins, which weakens the association of DNA withhistones, which make the DNA more accessible to transcription, thereby up-regulating transcription
histone deacetylase (HDAC) activity – deacetylateshistone proteins, which strengthens the association of DNA with histones, which make the DNA less accessible to transcription, thereby down-regulating transcription
Transcription factors are one of the groups of proteins that read and interpret the genetic "blueprint" in the DNA. They bind to the 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:
Other transcription factors differentially regulate the expression of various genes by binding toenhancer 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]
Many transcription factors inmulticellular organisms are involved in development.[23] Responding to stimuli, these transcription factors turn on/off the transcription of the appropriate genes, which, in turn, allows for changes in cellmorphology or activities needed forcell fate determination andcellular differentiation. TheHox transcription factor family, for example, is important for properbody pattern formation in organisms as diverse as fruit flies to humans.[24][25] Another example is the transcription factor encoded by thesex-determining region Y (SRY) gene, which plays a major role in determining sex in humans.[26]
Cells can communicate with each other by releasing molecules that producesignaling 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 theestrogen receptor transcription factor: Estrogen is secreted by tissues such as theovaries andplacenta, crosses thecell membrane of the recipient cell, and is bound by the estrogen receptor in the cell'scytoplasm. The estrogen receptor then goes to the cell'snucleus and binds to itsDNA-binding sites, changing the transcriptional regulation of the associated genes.[28]
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 includeheat shock factor (HSF), which upregulates genes necessary for survival at higher temperatures,[29]hypoxia inducible factor (HIF), which upregulates genes necessary for cell survival in low-oxygen environments,[30] andsterol regulatory element binding protein (SREBP), which helps maintain properlipid levels in the cell.[31]
Many transcription factors, especially some that areproto-oncogenes ortumor suppressors, help regulate thecell cycle and as such determine how large a cell will get and when it can divide into two daughter cells.[32][33] One example is theMyc oncogene, which has important roles incell growth andapoptosis.[34]
Transcription factors can also be used to alter gene expression in a host cell to promote pathogenesis. A well studied example of this are the transcription-activator like effectors (TAL effectors) secreted byXanthomonas bacteria. When injected into plants, these proteins can enter the nucleus of the plant cell, bind plant promoter sequences, and activate transcription of plant genes that aid in bacterial infection.[35] TAL effectors contain a central repeat region in which there is a simple relationship between the identity of two critical residues in sequential repeats and sequential DNA bases in the TAL effector's target site.[36][37] This property likely makes it easier for these proteins to evolve in order to better compete with the defense mechanisms of the host cell.[38]
It is common in biology for important processes to have multiple layers of regulation and control. This is 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:
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 anegative 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]
Ineukaryotes, transcription factors (like most proteins) are transcribed in thenucleus but are then translated in the cell'scytoplasm. Many proteins that are active in the nucleus containnuclear localization signals that direct them to the nucleus. But, for many transcription factors, this is a key point in their regulation.[40] Important classes of transcription factors such as somenuclear receptors must first bind aligand while in the cytoplasm before they can relocate to the nucleus.[40]
Transcription factors may be activated or deactivated through their signal-sensing or effector domains. However, not all transcription factors have an effector domain; for example, approximately 400 C2H2 zinc finger transcription factors contain only DNA-binding domains (DBDs).[5] Activation or repression of transcription factors can occur through 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 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).
In eukaryotes, DNA is organized with the help ofhistones into compact particles callednucleosomes, 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-calledpioneer 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 aschromatin 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 tocompete 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 samegene.[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 ascofactors that allow efficient recruitment of thepreinitiation complex andRNA 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 withNF-κB, which is a switch between inflammation and cellular differentiation; thereby steroids can affect the inflammatory response and function of certain tissues.[46]
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, aCpG 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]
TheDNA 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 (seeDNA demethylation). Multiple transcription factors important in cell differentiation and lineage specification, includingNANOG,SALL4A,WT1,EBF1,PU.1, andE2A, have been shown to recruit TET enzymes to specific genomic loci (primarily enhancers) to act on methylcytosine (mC) and convert it to hydroxymethylcytosine hmC (and in most cases marking them for subsequent complete demethylation to cytosine).[51] TET-mediated conversion of mC to hmC appears to disrupt the binding of 5mC-binding proteins includingMECP2 and MBD (Methyl-CpG-binding domain) proteins, facilitating nucleosome remodeling and the binding of transcription factors, thereby activating transcription of those genes.EGR1 is an important transcription factor inmemory formation. It has an essential role inbrainneuronepigenetic reprogramming. The transcription factorEGR1 recruits theTET1 protein that initiates a pathway ofDNA demethylation.[52] EGR1, together with TET1, is employed in programming the distribution of methylation sites on brain DNA during brain development and inlearning (seeEpigenetics in learning and memory).
Schematic diagram of the amino acid sequence (amino terminus to the left and carboxylic acid terminus to the right) of a prototypical transcription factor that contains (1) a DNA-binding domain (DBD), (2) signal-sensing domain (SSD), and Activation domain (AD). 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.Domain architecture example:Lactose Repressor (LacI). The N-terminal DNA binding domain (labeled) of thelac repressor binds its target DNA sequence (gold) in the major groove using ahelix-turn-helix motif. Effector molecule binding (green) occurs in the regulatory domain (labeled). This triggers an allosteric response mediated by the linker region (labeled).
Transcription factors are modular in structure and contain the followingdomains:[1]
DNA-binding domain (DBD), which attaches to specific sequences of DNA (enhancer orpromoter. Necessary component for all vectors. Used to drive transcription of the vector's transgenepromoter sequences) adjacent to regulated genes. DNA sequences that bind transcription factors are often referred to asresponse elements. Sometimes, DBDs can directly recruit transcription coregulators[53] without the need of an activation domain.
Activation domain (AD), which contains binding sites for other proteins such astranscription coregulators. These binding sites are frequently referred to asactivation functions (AFs),Transactivation domain (TAD) orTrans-activating domainTAD, not to be confused with topologically associating domain (TAD).[54] However, not all TFs have a activation domain (e.g., half of them (~800) are C2H2 zinc finger proteins)[5]
An optionalsignal-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.
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:
Transcription factors interact with their binding sites using a combination ofelectrostatic (of whichhydrogen bonds are a special case) andVan der Waals forces. Due to the nature of these chemical interactions, most transcription factors bind DNA in a sequence specific manner. However, not allbases 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 theconsensus binding site for theTATA-binding protein (TBP) is TATAAAA, the TBP transcription factor can also bind similar sequences such as TATATAT or TATATAA.[64]
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 thegenome of thecell. Other constraints, such as DNA accessibility in the cell or availability ofcofactors 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.
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.
Due to their important roles in development, intercellular signaling, and cell cycle, some human diseases have been associated withmutations in transcription factors.[65]
Many transcription factors are eithertumor suppressors oroncogenes, and, thus, mutations or aberrant regulation of them is associated with cancer. Three groups of transcription factors are known to be important in human cancer: (1) theNF-kappaB andAP-1 families, (2) theSTAT family and (3) thesteroid receptors.[66]
Mutations in theFOXP2 transcription factor are associated withdevelopmental verbal dyspraxia, a disease in which individuals are unable to produce the finely coordinated movements required for speech.[71]
Approximately 10% of currently prescribed drugs directly target thenuclear receptor class of transcription factors.[77] Examples includetamoxifen andbicalutamide for the treatment ofbreast andprostate cancer, respectively, and various types ofanti-inflammatory andanabolicsteroids.[78] In addition, transcription factors are often indirectly modulated by drugs throughsignaling cascades. It might be possible to directly target other less-explored transcription factors such asNF-κB with drugs.[79][80][81][82] Transcription factors outside the nuclear receptor family are thought to be more difficult to target withsmall molecule therapeutics since it is not clear that they are"drugable" but progress has been made on Pax2[83][84] and thenotch pathway.[85]
Gene duplications have played a crucial role in theevolution of species. This applies particularly to transcription factors. Once they occur as duplicates, accumulated mutations encoding for one copy can take place without negatively affecting the regulation of downstream targets. However, changes of the DNA binding specificities of the single-copyLeafy transcription factor, which occurs in most land plants, have recently been elucidated. In that respect, a single-copy transcription factor can undergo a change of specificity through a promiscuous intermediate without losing function. Similar mechanisms have been proposed in the context of all alternativephylogenetic hypotheses, and the role of transcription factors in the evolution of all species.[86][87]
The transcription factors have a role inresistance activity which is important for successfulbiocontrol activity. The resistant tooxidative stress and alkaline pH sensing were contributed from the transcription factor Yap1 and Rim101 of thePapiliotrema terrestris LS28 as molecular tools revealed an understanding of the genetic mechanisms underlying the biocontrol activity which supportsdisease management programs based on biological and integrated control.[88]
There are different technologies available to analyze transcription factors. On thegenomic level, DNA-sequencing and database research are commonly used.[89] The protein version of the transcription factor is detectable by using specificantibodies. The sample is detected on awestern blot. By usingelectrophoretic mobility shift assay (EMSA),[90] the activation profile of transcription factors can be detected. Amultiplex approach for activation profiling is a TF chip system where several different transcription factors can be detected in parallel.[91]
The most commonly used method for identifying transcription factor binding sites ischromatin immunoprecipitation (ChIP).[92] This technique relies on chemical fixation of chromatin withformaldehyde, followed by co-precipitation of DNA and the transcription factor of interest using anantibody that specifically targets that protein. The DNA sequences can then be identified by microarray or high-throughput sequencing (ChIP-seq) to determine transcription factor binding sites. If no antibody is available for the protein of interest,DamID may be a convenient alternative.[93]
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.[94][95]
Upstream transcription factors are proteins that bind somewhere upstream of the initiation site to stimulate or repress transcription. These are roughly synonymous withspecific transcription factors, because they vary considerably depending on whatrecognition sequences are present in the proximity of the gene.[97]
Transcription factors have been classified according to their regulatory function:[14]
I.Constitutive – present in all cells at all times, constantly active, all beingactivators. 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 factors,Sp1,NF1,CCAAT
II.ADevelopmental(cell-type specific) – beginning in a fertilized egg. Once expressed, require no additional activation. E.g.:GATA,HNF,PIT-1,MyoD,Myf5,Hox,Winged Helix
II.BSignal-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.2Intracellular ligand (autocrine)-dependent – activated by small intracellular molecules. E.g.:SREBP,p53, orphan nuclear receptors.
II.B.3Cell 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:
Receptor tyrosine kinases upon ligand binding trigger other pathways that finally terminate in serine phosphorylation of the abundant resident nuclear transcription factors.
II.B.3.bLatent cytoplasmic factors – residing in the cytoplasm when inactive. Structurally and chemically very diverse group, and so are their activation pathways. E.g.:STAT,R-SMAD,NF-κB,Notch,TUBBY,NFAT
Transcription factors are often classified based on thesequence similarity and hence thetertiary structure of their DNA-binding domains.[98][13][99][12] The following classification is based on the 3D structure of theirDBD and the way it contacts DNA. It was first developed for Human TF and later extended to rodents[94] and also to plants.[95]
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
^Roeder RG (September 1996). "The role of general initiation factors in transcription by RNA polymerase II".Trends in Biochemical Sciences.21 (9):327–35.doi:10.1016/S0968-0004(96)10050-5.PMID8870495.
^Thomas MC, Chiang CM (2006). "The general transcription machinery and general cofactors".Critical Reviews in Biochemistry and Molecular Biology.41 (3):105–78.doi:10.1080/10409230600648736.PMID16858867.S2CID13073440.
^Pawson T (1993). "Signal transduction--a conserved pathway from the membrane to the nucleus".Developmental Genetics.14 (5):333–8.doi:10.1002/dvg.1020140502.PMID8293575.
^Osborne CK, Schiff R, Fuqua SA, Shou J (December 2001). "Estrogen receptor: current understanding of its activation and modulation".Clinical Cancer Research.7 (12 Suppl):4338s –4342s, discussion 4411s–4412s.PMID11916222.
^Meyyappan M, Atadja PW, Riabowol KT (1996). "Regulation of gene expression and transcription factor binding activity during cellular aging".Biological Signals.5 (3):130–8.doi:10.1159/000109183.PMID8864058.
^Evan G, Harrington E, Fanidi A, Land H, Amati B, Bennett M (August 1994). "Integrated control of cell proliferation and cell death by the c-myc oncogene".Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences.345 (1313):269–75.Bibcode:1994RSPTB.345..269E.doi:10.1098/rstb.1994.0105.PMID7846125.
^abWhiteside ST, Goodbourn S (April 1993). "Signal transduction and nuclear targeting: regulation of transcription factor activity by subcellular localisation".Journal of Cell Science.104 (4):949–55.doi:10.1242/jcs.104.4.949.PMID8314906.
^Bohmann D (November 1990). "Transcription factor phosphorylation: a link between signal transduction and the regulation of gene expression".Cancer Cells.2 (11):337–44.PMID2149275.
^Amoutzias GD, Robertson DL, Van de Peer Y, Oliver SG (May 2008). "Choose your partners: dimerization in eukaryotic transcription factors".Trends in Biochemical Sciences.33 (5):220–9.doi:10.1016/j.tibs.2008.02.002.PMID18406148.
^Copland JA, Sheffield-Moore M, Koldzic-Zivanovic N, Gentry S, Lamprou G, Tzortzatou-Stathopoulou F, et al. (June 2009). "Sex steroid receptors in skeletal differentiation and epithelial neoplasia: is tissue-specific intervention possible?".BioEssays.31 (6):629–41.doi:10.1002/bies.200800138.PMID19382224.S2CID205469320.
^Weber M, Hellmann I, Stadler MB, Ramos L, Pääbo S, Rebhan M, et al. (April 2007). "Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome".Nat. Genet.39 (4):457–66.doi:10.1038/ng1990.PMID17334365.S2CID22446734.
^Sun Z, Xu X, He J, Murray A, Sun MA, Wei X, Wang X, McCoig E, Xie E, Jiang X, Li L, Zhu J, Chen J, Morozov A, Pickrell AM, Theus MH, Xie H. EGR1 recruits TET1 to shape the brain methylome during development and upon neuronal activity. Nat Commun. 2019 Aug 29;10(1):3892. doi: 10.1038/s41467-019-11905-3. PMID 31467272
^Wintjens R, Rooman M (September 1996). "Structural classification of HTH DNA-binding domains and protein-DNA interaction modes".Journal of Molecular Biology.262 (2):294–313.doi:10.1006/jmbi.1996.0514.PMID8831795.
^Laity JH, Lee BM, Wright PE (February 2001). "Zinc finger proteins: new insights into structural and functional diversity".Current Opinion in Structural Biology.11 (1):39–46.doi:10.1016/S0959-440X(00)00167-6.PMID11179890.
^Wolfe SA, Nekludova L, Pabo CO (2000). "DNA recognition by Cys2His2 zinc finger proteins".Annual Review of Biophysics and Biomolecular Structure.29:183–212.doi:10.1146/annurev.biophys.29.1.183.PMID10940247.
^Libermann TA, Zerbini LF (February 2006). "Targeting transcription factors for cancer gene therapy".Current Gene Therapy.6 (1):17–33.doi:10.2174/156652306775515501.PMID16475943.
^Moretti P, Zoghbi HY (June 2006). "MeCP2 dysfunction in Rett syndrome and related disorders".Current Opinion in Genetics & Development.16 (3):276–81.doi:10.1016/j.gde.2006.04.009.PMID16647848.
^Lennon PA, Cooper ML, Peiffer DA, Gunderson KL, Patel A, Peters S, et al. (April 2007). "Deletion of 7q31.1 supports involvement ofFOXP2 in language impairment: clinical report and review".American Journal of Medical Genetics. Part A.143A (8):791–8.doi:10.1002/ajmg.a.31632.PMID17330859.S2CID22021740.
^Overington JP, Al-Lazikani B, Hopkins AL (December 2006). "How many drug targets are there?".Nature Reviews. Drug Discovery.5 (12):993–6.doi:10.1038/nrd2199.PMID17139284.S2CID11979420.
^Gronemeyer H, Gustafsson JA, Laudet V (November 2004). "Principles for modulation of the nuclear receptor superfamily".Nature Reviews. Drug Discovery.3 (11):950–64.doi:10.1038/nrd1551.PMID15520817.S2CID205475111.
^Bustin SA, McKay IA (June 1994). "Transcription factors: targets for new designer drugs".British Journal of Biomedical Science.51 (2):147–57.PMID8049612.
^Papavassiliou AG (August 1998). "Transcription-factor-modulating agents: precision and selectivity in drug design".Molecular Medicine Today.4 (8):358–66.doi:10.1016/S1357-4310(98)01303-3.PMID9755455.
^Ghosh D, Papavassiliou AG (2005). "Transcription factor therapeutics: long-shot or lodestone".Current Medicinal Chemistry.12 (6):691–701.doi:10.2174/0929867053202197.PMID15790306.
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.doi:10.1104/pp.110.153593.ISSN0032-0889
