5449
63-398: 18736 ENSG00000064835 ENSMUSG00000004842 P28069 Q00286 NM_001122757 NM_000306 NM_008849 NM_001362468 NP_000297 NP_001116229 NP_032875 NP_001349397 POU class 1 homeobox 1 , also known as pituitary-specific positive transcription factor 1 ( PIT1 ), POU domain, class 1, transcription factor 1 ( POU1F1 ) and growth hormone factor 1 (GHF1),
126-496: A beta-sheet structure with large connecting loops, which serve to recognize either DNA major grooves or antigens. Usually found in immunoglobulin proteins, they are also present in Stat proteins of the cytokine pathway. This is likely because the cytokine pathway evolved relatively recently and has made use of systems that were already functional, rather than creating its own. The B3 DBD ( InterPro : IPR003340 , SCOP 117343 )
189-503: 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 these sequences tend to be short, potential transcription factor binding sites can occur by chance if
252-449: 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
315-421: A host cell to promote pathogenesis. A well studied example of this are the transcription-activator like effectors ( TAL effectors ) secreted by Xanthomonas 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. TAL effectors contain a central repeat region in which there
378-585: A larger protein consisting of further protein domains with differing function. The extra domains often regulate the activity of the DNA-binding domain. The function of DNA binding is either structural or involves transcription regulation , with the two roles sometimes overlapping. DNA-binding domains with functions involving DNA structure have biological roles in DNA replication , repair , storage , and modification, such as methylation . Many proteins involved in
441-773: 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 with mutations in transcription factors. Many transcription factors are either tumor suppressors or oncogenes , and, thus, mutations or aberrant regulation of them
504-563: A loop. One helix is typically smaller and due to the flexibility of the loop, allows dimerization by folding and packing against another helix. The larger helix typically contains the DNA-binding regions. HMG-box domains are found in high mobility group proteins which are involved in a variety of DNA-dependent processes like replication and transcription. They also alter the flexibility of the DNA by inducing bends. The domain consists of three alpha helices separated by loops. Wor3 domains, named after
567-417: A major role in determining sex in humans. 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. Estrogen signaling is an example of a fairly short signaling cascade that involves
630-853: 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. TET enzymes do not specifically bind to methylcytosine except when recruited (see DNA demethylation ). Multiple transcription factors important in cell differentiation and lineage specification, including NANOG , SALL4 A, WT1 , EBF1 , PU.1 , and E2A , 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). TET-mediated conversion of mC to hmC appears to disrupt
693-525: A rather small number of protein families are DNA-binding. For instance, more than 2000 of the ~20,000 human proteins are "DNA-binding", including about 750 Zinc-finger proteins. Originally discovered in bacteria, the helix-turn-helix motif is commonly found in repressor proteins and is about 20 amino acids long. In eukaryotes, the homeodomain comprises 2 helices, one of which recognizes the DNA (aka recognition helix). They are common in proteins that regulate developmental processes. The zinc finger domain
SECTION 10
#1732859256353756-452: A smaller number. 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,
819-402: A somewhat specific DNA cleavage pattern that can be useful for studying DNA recognition by a technique called DNA footprinting . Many DNA-binding domains must recognize specific DNA sequences, such as DBDs of transcription factors that activate specific genes, or those of enzymes that modify DNA at specific sites, like restriction enzymes and telomerase . The hydrogen bonding pattern in
882-548: A specific sequence of DNA adjacent to the genes that they regulate. TFs are grouped into classes based on their DBDs. Other proteins such as coactivators , chromatin remodelers , histone acetyltransferases , histone deacetylases , kinases , and methylases are also essential to gene regulation, but lack DNA-binding domains, and therefore are not TFs. TFs are of interest in medicine because TF mutations can cause specific diseases, and medications can be potentially targeted toward them. Transcription factors are essential for
945-419: Is chromatin immunoprecipitation (ChIP). This technique relies on chemical fixation of chromatin with formaldehyde , followed by co-precipitation of DNA and the transcription factor of interest using an antibody 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
1008-453: Is a stub . You can help Misplaced Pages by expanding it . Transcription factor In molecular biology , a transcription factor ( TF ) (or sequence-specific DNA-binding factor ) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA , by binding to a specific DNA sequence . The function of TFs is to regulate—turn on and off—genes in order to make sure that they are expressed in
1071-509: Is a transcription factor for growth hormone encoded by the gene POU1F1 . PIT1 is part of the POU family of transcription factors. It is expressed by somatotrophic cells, as well as thyrotrophs and lactotrophs of the anterior pituitary gland. It contains a C-terminal domain for transactivation. Another domain is DNA binding—its C-terminal portion is homologous to the homeodomain consensus, common to many genes involved in development, while
1134-447: 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. This property likely makes it easier for these proteins to evolve in order to better compete with the defense mechanisms of the host cell. It is common in biology for important processes to have multiple layers of regulation and control. This
1197-455: 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
1260-525: Is associated with cancer. Three groups of transcription factors are known to be important in human cancer: (1) the NF-kappaB and AP-1 families, (2) the STAT family and (3) the steroid receptors . Below are a few of the better-studied examples: Approximately 10% of currently prescribed drugs directly target the nuclear receptor class of transcription factors. Examples include tamoxifen and bicalutamide for
1323-595: Is available for the protein of interest, DamID may be a convenient alternative. 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. There are two mechanistic classes of transcription factors: Transcription factors have been classified according to their regulatory function: Transcription factors are often classified based on
SECTION 20
#17328592563531386-442: Is called its DNA-binding domain. Below is a partial list of some of the major families of DNA-binding domains/transcription factors: The DNA sequence that a transcription factor binds to is called a transcription factor-binding site or response element . 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
1449-403: 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, while methylation of CpGs in the body of a gene increases expression. 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
1512-401: Is found exclusively in transcription factors from higher plants and restriction endonucleases EcoRII and BfiI and typically consists of 100-120 residues. It includes seven beta sheets and two alpha helices , which form a DNA-binding pseudobarrel protein fold . TAL effectors are found in bacterial plant pathogens of the genus Xanthomonas and are involved in regulating the genes of
1575-478: Is found mainly in eukaryotes and to a limited extent in bacteria. The bZIP domain contains an alpha helix with a leucine at every 7th amino acid. If two such helices find one another, the leucines can interact as the teeth in a zipper, allowing dimerization of two proteins. When binding to the DNA, basic amino acid residues bind to the sugar-phosphate backbone while the helices sit in the major grooves. It regulates gene expression. Consisting of about 110 amino acids,
1638-651: Is mostly found in eukaryotes, but some examples have been found in bacteria. The zinc finger domain is generally between 23 and 28 amino acids long and is stabilized by coordinating zinc ions with regularly spaced zinc-coordinating residues (either histidines or cysteines). The most common class of zinc finger (Cys2His2) coordinates a single zinc ion and consists of a recognition helix and a 2-strand beta-sheet. In transcription factors these domains are often found in arrays (usually separated by short linker sequences) and adjacent fingers are spaced at 3 basepair intervals when bound to DNA. The basic leucine zipper ( bZIP ) domain
1701-409: Is not clear that they are "drugable" but progress has been made on Pax2 and the notch pathway. Gene duplications have played a crucial role in the evolution 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
1764-414: 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,
1827-461: The TET1 protein that initiates a pathway of DNA demethylation . EGR1, together with TET1, is employed in programming the distribution of methylation sites on brain DNA during brain development and in learning (see Epigenetics in learning and memory ). Transcription factors are modular in structure and contain the following domains : The portion ( domain ) of the transcription factor that binds DNA
1890-920: 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. 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 heat shock factor (HSF), which upregulates genes necessary for survival at higher temperatures, hypoxia inducible factor (HIF), which upregulates genes necessary for cell survival in low-oxygen environments, and sterol regulatory element binding protein (SREBP), which helps maintain proper lipid levels in
1953-566: The genomic level, DNA- sequencing and database research are commonly used. The protein version of the transcription factor is detectable by using specific antibodies . The sample is detected on a western blot . By using electrophoretic mobility shift assay (EMSA), 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. The most commonly used method for identifying transcription factor binding sites
Pituitary-specific positive transcription factor 1 - Misplaced Pages Continue
2016-468: The human genome . Transcription factors are members of the proteome as well as regulome . TFs work alone or with other proteins in a complex, by promoting (as an activator ), or blocking (as a repressor ) the recruitment of RNA polymerase (the enzyme that performs the transcription of genetic information from DNA to RNA) to specific genes. A defining feature of TFs is that they contain at least one DNA-binding domain (DBD), which attaches to
2079-427: 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
2142-493: The regulation of gene expression contain DNA-binding domains. For example, proteins that regulate transcription by binding DNA are called transcription factors . The final output of most cellular signaling cascades is gene regulation. The DBD interacts with the nucleotides of DNA in a DNA sequence-specific or non-sequence-specific manner, but even non-sequence-specific recognition involves some sort of molecular complementarity between protein and DNA. DNA recognition by
2205-456: The sequence similarity and hence the tertiary structure of their DNA-binding domains. The following classification is based of the 3D structure of their DBD and the way it contacts DNA. It was first developed for Human TF and later extended to rodents and also to plants. There are numerous databases cataloging information about transcription factors, but their scope and utility vary dramatically. Some may contain only information about
2268-445: The winged helix (WH) domain has four helices and a two-strand beta-sheet. The winged helix-turn-helix (wHTH) domain SCOP 46785 is typically 85-90 amino acids long. It is formed by a 3-helical bundle and a 4-strand beta-sheet (wing). The basic helix-loop-helix (bHLH) domain is found in some transcription factors and is characterized by two alpha helices (α-helixes) connected by
2331-505: The DBD can occur at the major or minor groove of DNA, or at the sugar-phosphate DNA backbone (see the structure of DNA ). Each specific type of DNA recognition is tailored to the protein's function. For example, the DNA-cutting enzyme DNAse I cuts DNA almost randomly and so must bind to DNA in a non-sequence-specific manner. But, even so, DNAse I recognizes a certain 3-D DNA structure , yielding
2394-431: The DNA binding specificities of the single-copy Leafy 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 alternative phylogenetic hypotheses, and the role of transcription factors in
2457-674: The DNA major groove is less degenerate than that of the DNA minor groove, providing a more attractive site for sequence -specific DNA recognition. The specificity of DNA-binding proteins can be studied using many biochemical and biophysical techniques, such as gel electrophoresis , analytical ultracentrifugation , calorimetry , DNA mutation , protein structure mutation or modification, nuclear magnetic resonance , x-ray crystallography , surface plasmon resonance , electron paramagnetic resonance , cross-linking and microscale thermophoresis (MST). A large fraction of genes in each genome encodes DNA-binding proteins (see Table). However, only
2520-411: 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. In eukaryotes , transcription factors (like most proteins) are transcribed in the nucleus but are then translated in the cell's cytoplasm . Many proteins that are active in the nucleus contain nuclear localization signals that direct them to
2583-430: 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
Pituitary-specific positive transcription factor 1 - Misplaced Pages Continue
2646-488: The DNA-binding interaction. Each repeat within the array takes the form of paired alpha-helices, while the whole repeat array forms a right-handed superhelix, wrapping around the DNA-double helix. TAL effector repeat arrays have been shown to contract upon DNA binding and a two-state search mechanism has been proposed whereby the elongated TALE begins to contract around the DNA beginning with a successful Thymine recognition from
2709-863: The White–Opaque Regulator 3 (Wor3) in Candida albicans arose more recently in evolutionary time than most previously described DNA-binding domains and are restricted to a small number of fungi. The OB-fold is a small structural motif originally named for its o ligonucleotide / o ligosaccharide b inding properties. OB-fold domains range between 70 and 150 amino acids in length. OB-folds bind single-stranded DNA, and hence are single-stranded binding proteins . OB-fold proteins have been identified as critical for DNA replication , DNA recombination , DNA repair , transcription , translation , cold shock response , and telomere maintenance. The immunoglobulin domain ( InterPro : IPR013783 ) consists of
2772-557: The actual proteins, some about their binding sites, or about their target genes. Examples include the following: DNA-binding domain A DNA-binding domain ( DBD ) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA . A DBD can recognize a specific DNA sequence (a recognition sequence ) or have a general affinity to DNA. Some DNA-binding domains may also include nucleic acids in their folded structure. One or more DNA-binding domains are often part of
2835-467: The adjacent gene is either up- or down-regulated . Transcription factors use a variety of mechanisms for the regulation of gene expression. These mechanisms include: 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
2898-411: The binding of 5mC-binding proteins including MECP2 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 in memory formation. It has an essential role in brain neuron epigenetic reprogramming. The transcription factor EGR1 recruits
2961-447: The cell. Many transcription factors, especially some that are proto-oncogenes or tumor suppressors , help regulate the cell cycle and as such determine how large a cell will get and when it can divide into two daughter cells. One example is the Myc oncogene, which has important roles in cell growth and apoptosis . Transcription factors can also be used to alter gene expression in
3024-408: 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 . Transcription factors bind to either enhancer or promoter regions of DNA adjacent to the genes that they regulate based on recognizing specific DNA motifs. Depending on the transcription factor, the transcription of
3087-436: The desired cells 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 direct cell division , cell growth , and cell death throughout life; cell migration and organization ( body plan ) during embryonic development; and intermittently in response to signals from outside the cell, such as a hormone . There are approximately 1600 TFs in
3150-647: The evolution of all species. The transcription factors have a role in resistance activity which is important for successful 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. There are different technologies available to analyze transcription factors. On
3213-535: The gene that they regulate. 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. Many transcription factors in multicellular organisms are involved in development. Responding to stimuli, these transcription factors turn on/off
SECTION 50
#17328592563533276-469: The gene. The DNA binding sites of 519 transcription factors were evaluated. 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
3339-465: The host plant in order to facilitate bacterial virulence, proliferation, and dissemination. They contain a central region of tandem 33-35 residue repeats and each repeat region encodes a single DNA base in the TALE's binding site. Within the repeat it is residue 13 alone that directly contacts the DNA base, determining sequence specificity, while other positions make contacts with the DNA backbone, stabilising
3402-594: The important functions and biological roles transcription factors are involved in: In eukaryotes , an important class of transcription factors called general transcription factors (GTFs) are necessary for transcription to occur. Many of these GTFs do not actually bind DNA, but rather are part of the large transcription preinitiation complex that interacts with RNA polymerase directly. The most common GTFs are TFIIA , TFIIB , TFIID (see also TATA binding protein ), TFIIE , TFIIF , and TFIIH . The preinitiation complex binds to promoter regions of DNA upstream to
3465-432: 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
3528-530: The nucleosome should be actively unwound by molecular motors such as chromatin remodelers . 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. Pairs of transcription factors and other proteins can play antagonistic roles (activator versus repressor) in
3591-415: The nucleus. But, for many transcription factors, this is a key point in their regulation. Important classes of transcription factors such as some nuclear receptors must first bind a ligand while in the cytoplasm before they can relocate to the nucleus. Transcription factors may be activated (or deactivated) through their signal-sensing domain by a number of mechanisms including: In eukaryotes, DNA
3654-414: The other portion is POU specific, affords PIT1 specificity in its transcriptional activation of the prolactin and growth hormone genes and is involved in protein-protein interactions. Activity on thyroid stimulating hormone-beta expression is also known for PIT1. Pituitary-specific positive transcription factor 1 has been shown to interact with GATA2 and PITX1 . This biochemistry article
3717-503: 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. Transcription factors and methylated cytosines in DNA both have major roles in regulating gene expression. (Methylation of cytosine in DNA primarily occurs where cytosine
3780-455: 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. 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, though other studies indicate it to be
3843-425: The regulation of the same gene . Most transcription factors do not work alone. Many large TF families form complex homotypic or heterotypic interactions through dimerization. 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
SECTION 60
#17328592563533906-447: The transcription of the appropriate genes, which, in turn, allows for changes in cell morphology or activities needed for cell fate determination and cellular differentiation . The Hox transcription factor family, for example, is important for proper body pattern formation in organisms as diverse as fruit flies to humans. Another example is the transcription factor encoded by the sex-determining region Y (SRY) gene, which plays
3969-495: The treatment of breast and prostate cancer , respectively, and various types of anti-inflammatory and anabolic steroids . In addition, transcription factors are often indirectly modulated by drugs through signaling cascades . It might be possible to directly target other less-explored transcription factors such as NF-κB with drugs. Transcription factors outside the nuclear receptor family are thought to be more difficult to target with small molecule therapeutics since it
#352647