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In
molecular biology Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...
, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of
transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...
of genetic information from DNA to
messenger RNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the p ...
, by binding to a specific
DNA sequence DNA sequencing is the process of determining the nucleic acid sequence – the order of nucleotides in DNA. It includes any method or technology that is used to determine the order of the four bases: adenine, guanine, cytosine, and thymine. The ...
. The function of TFs is to regulate—turn on and off—genes in order to make sure that they are expressed in the desired
cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
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 division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there a ...
,
cell growth Cell growth refers to an increase in the total mass of a cell, including both cytoplasmic, nuclear and organelle volume. Cell growth occurs when the overall rate of cellular biosynthesis (production of biomolecules or anabolism) is greater than ...
, and
cell death Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as dis ...
throughout life;
cell migration Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular direct ...
and organization (
body plan A body plan, ( ), or ground plan is a set of morphological features common to many members of a phylum of animals. The vertebrates share one body plan, while invertebrates have many. This term, usually applied to animals, envisages a "blueprin ...
) during embryonic development; and intermittently in response to signals from outside the cell, such as a
hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required fo ...
. There are up to 1600 TFs in the
human genome The human genome is a complete set of nucleic acid sequences for humans, encoded as DNA within the 23 chromosome pairs in cell nuclei and in a small DNA molecule found within individual Mitochondrial DNA, mitochondria. These are usually treated s ...
. Transcription factors are members of the
proteome The proteome is the entire set of proteins that is, or can be, expressed by a genome, cell, tissue, or organism at a certain time. It is the set of expressed proteins in a given type of cell or organism, at a given time, under defined conditions ...
as well as
regulome Regulome refers to the whole set of regulatory components in a cell. Those components can be regulatory elements, genes, mRNAs, proteins, and metabolites. The description includes the interplay of regulatory effects between these components, and t ...
. TFs work alone or with other proteins in a complex, by promoting (as an activator), or blocking (as a
repressor In molecular genetics, a repressor is a DNA- or RNA-binding protein that inhibits the expression of one or more genes by binding to the operator or associated silencers. A DNA-binding repressor blocks the attachment of RNA polymerase to the ...
) the recruitment of
RNA polymerase In molecular biology, RNA polymerase (abbreviated RNAP or RNApol), or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that synthesizes RNA from a DNA template. Using the enzyme helicase, RNAP locally opens the ...
(the enzyme that performs the
transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...
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 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 genera ...
(DBD), which attaches to 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 acetyltransferase Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-''N''-acetyllysine. DNA is wrapped around histones, and, by transferring an ...
s,
histone deacetylase Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
s,
kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule dona ...
s, and
methylase Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Ross ...
s 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.


Number

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. There are approximately 2800 proteins in the
human genome The human genome is a complete set of nucleic acid sequences for humans, encoded as DNA within the 23 chromosome pairs in cell nuclei and in a small DNA molecule found within individual Mitochondrial DNA, mitochondria. These are usually treated s ...
that contain DNA-binding domains, and 1600 of these are presumed to function as transcription factors, though other studies indicate it to be 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 Hepatocyte nuclear factors (HNFs) are a group of phylogenetically unrelated transcription factors that regulate the transcription of a diverse group of genes into proteins. These proteins include blood clotting factors and in addition, enzymes an ...
). 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 Development or developing may refer to: Arts *Development hell, when a project is stuck in development *Filmmaking, development phase, including finance and budgeting *Development (music), the process thematic material is reshaped *Photographi ...
.


Mechanism

Transcription factors bind to either enhancer or promoter regions of DNA adjacent to the genes that they regulate. Depending on the transcription factor, the transcription of 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: * stabilize or block the binding of RNA polymerase to DNA * catalyze the
acetylation : In organic chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply ''acetates''. Deacetylation is the opposit ...
or deacetylation of
histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are ...
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: **
histone acetyltransferase Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-''N''-acetyllysine. DNA is wrapped around histones, and, by transferring an ...
(HAT) activity – acetylates
histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are ...
proteins, which weakens the association of DNA with
histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are ...
s, which make the DNA more accessible to transcription, thereby up-regulating transcription **
histone deacetylase Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
(HDAC) activity – deacetylates
histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are ...
proteins, which strengthens the association of DNA with histones, which make the DNA less accessible to transcription, thereby down-regulating transcription * recruit
coactivator A coactivator is a type of transcriptional coregulator that binds to an activator (a transcription factor) to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA ...
or
corepressor In the field of molecular biology, a corepressor is a molecule that represses the expression of genes. In prokaryotes, corepressors are small molecules whereas in eukaryotes, corepressors are proteins. A corepressor does not directly bind to DNA, ...
proteins to the transcription factor DNA complex


Function

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:


Basal transcriptional regulation

In
eukaryote Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...
s, an important class of transcription factors called
general transcription factor General transcription factors (GTFs), also known as basal transcriptional factors, are a class of protein transcription factors that bind to specific sites ( promoter) on DNA to activate transcription of genetic information from DNA to messenger ...
s (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 The preinitiation complex (abbreviated PIC) is a complex of approximately 100 proteins that is necessary for the transcription of protein-coding genes in eukaryotes and archaea. The preinitiation complex positions RNA polymerase II at gene tran ...
that interacts with
RNA polymerase In molecular biology, RNA polymerase (abbreviated RNAP or RNApol), or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that synthesizes RNA from a DNA template. Using the enzyme helicase, RNAP locally opens the ...
directly. The most common GTFs are
TFIIA Transcription factor TFIIA is a nuclear protein involved in the RNA polymerase II-dependent transcription of DNA. TFIIA is one of several general (basal) transcription factors (GTFs) that are required for all transcription events that use RNA p ...
,
TFIIB Transcription factor II B (TFIIB) is a general transcription factor that is involved in the formation of the RNA polymerase II preinitiation complex (PIC) and aids in stimulating transcription initiation. TFIIB is localised to the nucleus and pro ...
,
TFIID Transcription factor II D (TFIID) is one of several general transcription factors that make up the RNA polymerase II preinitiation complex. RNA polymerase II holoenzyme is a form of eukaryotic RNA polymerase II that is recruited to the promoters ...
(see also
TATA binding protein The TATA-binding protein (TBP) is a general transcription factor that binds specifically to a DNA sequence called the TATA box. This DNA sequence is found about 30 base pairs upstream of the transcription start site in some eukaryotic gene p ...
),
TFIIE Transcription factor II E (TFIIE) is one of several general transcription factors that make up the RNA polymerase II preinitiation complex. It is a tetramer of two alpha and two beta chains and interacts with TAF6/TAFII80, ATF7IP, and varicella ...
,
TFIIF Transcription factor II F (TFIIF) is one of several general transcription factors that make up the RNA polymerase II preinitiation complex. TFIIF is encoded by the , , and genes. TFIIF binds to RNA polymerase II RNA polymerase II (RNAP II ...
, and
TFIIH Transcription factor II Human (transcription factor II H; TFIIH) is an important protein complex, having roles in transcription of various protein-coding genes and DNA nucleotide excision repair (NER) pathways. TFIIH first came to light in 1989 ...
. The preinitiation complex binds to promoter regions of DNA upstream to the gene that they regulate.


Differential enhancement of transcription

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.


Development

Many transcription factors in
multicellular organism A multicellular organism is an organism that consists of more than one cell, in contrast to unicellular organism. All species of animals, land plants and most fungi are multicellular, as are many algae, whereas a few organisms are partially uni- ...
s are involved in development. Responding to stimuli, these transcription factors turn on/off the transcription of the appropriate genes, which, in turn, allows for changes in cell
morphology Morphology, from the Greek and meaning "study of shape", may refer to: Disciplines *Morphology (archaeology), study of the shapes or forms of artifacts *Morphology (astronomy), study of the shape of astronomical objects such as nebulae, galaxies, ...
or activities needed for
cell fate determination Within the field of developmental biology, one goal is to understand how a particular cell develops into a final cell type, known as fate determination. Within an embryo, several processes play out at the cellular and tissue level to create an organ ...
and
cellular differentiation Cellular differentiation is the process in which a stem cell alters from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular ...
. 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 a major role in determining sex in humans.


Response to intercellular signals

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 Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal activ ...
signaling is an example of a fairly short signaling cascade that involves the
estrogen receptor Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen ( 17β-estradiol). Two classes of ER exist: nuclear estrogen receptors (ERα and ERβ), which are members of the ...
transcription factor: Estrogen is secreted by tissues such as the
ovaries The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...
and
placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mater ...
, crosses the cell membrane of the recipient cell, and is bound by the estrogen receptor in the cell's
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. Th ...
. The estrogen receptor then goes to the cell's
nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucle ...
and binds to its DNA-binding sites, changing the transcriptional regulation of the associated genes.


Response to environment

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 Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia. They are only present in parahoxozoan animals. Discovery The HIF transcriptional complex wa ...
(HIF), which upregulates genes necessary for cell survival in low-oxygen environments, and
sterol regulatory element binding protein Sterol regulatory element-binding proteins (SREBPs) are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes ''SREBF1'' and '' SREBF2''. SREBPs belong to the basic- ...
(SREBP), which helps maintain proper
lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...
levels in the cell.


Cell cycle control

Many transcription factors, especially some that are
proto-oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
s or tumor suppressors, help regulate the
cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
and as such determine how large a cell will get and when it can divide into two daughter cells. One example is the
Myc ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' ( MYC), ''l-myc'' (MYCL), and ''n-myc'' ( MYCN). ''c-myc'' (also sometimes refe ...
oncogene, which has important roles in
cell growth Cell growth refers to an increase in the total mass of a cell, including both cytoplasmic, nuclear and organelle volume. Cell growth occurs when the overall rate of cellular biosynthesis (production of biomolecules or anabolism) is greater than ...
and
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes includ ...
.


Pathogenesis

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 effector TAL (transcription activator-like) effectors (often referred to as TALEs, but not to be confused with the three amino acid loop extension homeobox class of proteins) are proteins secreted by some β- and γ-proteobacteria. Most of these are Xan ...
s) secreted by
Xanthomonas ''Xanthomonas'' (from greek: ''xanthos'' – “yellow”; ''monas'' – “entity”) is a genus of bacteria, many of which cause plant diseases. There are at least 27 plant associated ''Xanthomonas spp.'', that all together infect at least 400 ...
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 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.


Regulation

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:


Synthesis

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 a
negative feedback Negative feedback (or balancing feedback) occurs when some function of the output of a system, process, or mechanism is fed back in a manner that tends to reduce the fluctuations in the output, whether caused by changes in the input or by othe ...
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.


Nuclear localization

In
eukaryote Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...
s, transcription factors (like most proteins) are transcribed in the
nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucle ...
but are then translated in the cell's
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. Th ...
. Many proteins that are active in the nucleus contain
nuclear localization signal A nuclear localization signal ''or'' sequence (NLS) is an amino acid sequence that 'tags' a protein for import into the cell nucleus by nuclear transport. Typically, this signal consists of one or more short sequences of positively charged lysines o ...
s that direct them to the nucleus. But, for many transcription factors, this is a key point in their regulation. Important classes of transcription factors such as some
nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of spec ...
s must first bind a
ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electro ...
while in the cytoplasm before they can relocate to the nucleus.


Activation

Transcription factors may be activated (or deactivated) through their signal-sensing domain by a number of mechanisms including: *
ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electro ...
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 receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of spec ...
s). *
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
– Many transcription factors such as
STAT protein STAT, Stat. , or stat may refer to: * Stat (system call), a Unix system call that returns file attributes of an inode * ''Stat'' (TV series), an American sitcom that aired in 1991 * Stat (website), a health-oriented news website * STAT protein, a ...
s must be
phosphorylated In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...
before they can bind DNA. * interaction with other transcription factors (''e.g.'', homo- or hetero-
dimerization A dimer () ('' di-'', "two" + ''-mer'', "parts") is an oligomer consisting of two monomers joined by bonds that can be either strong or weak, covalent or intermolecular. Dimers also have significant implications in polymer chemistry, inorganic che ...
) or coregulatory proteins


Accessibility of DNA-binding site

In eukaryotes, DNA is organized with the help of
histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are ...
s into compact particles called
nucleosome A nucleosome is the basic structural unit of DNA packaging in eukaryotes. The structure of a nucleosome consists of a segment of DNA wound around eight histone proteins and resembles thread wrapped around a spool. The nucleosome is the fundamen ...
s, 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 factor Pioneer factors are transcription factors that can directly bind condensed chromatin. They can have positive and negative effects on transcription and are important in recruiting other transcription factors and histone modification enzymes as well ...
s 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 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 the regulation of the same
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.


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. 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 Cofactor may also refer to: * Cofactor (biochemistry), a substance that needs to be present in addition to an enzyme for a certain reaction to be catalysed * A domain parameter in elliptic curve cryptography, defined as the ratio between the order ...
that allow efficient recruitment of the preinitiation complex and
RNA polymerase In molecular biology, RNA polymerase (abbreviated RNAP or RNApol), or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that synthesizes RNA from a DNA template. Using the enzyme helicase, RNAP locally opens the ...
. 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 with
NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
, which is a switch between inflammation and cellular differentiation; thereby steroids can affect the inflammatory response and function of certain tissues.


Interaction with methylated cytosine

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, a
CpG site The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG isl ...
.) 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 The TET enzymes are a family of ten-eleven translocation (TET) methylcytosine dioxygenases. They are instrumental in DNA demethylation. 5-Methylcytosine (see first Figure) is a methylated form of the DNA base cytosine (C) that often regulates g ...
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. The
DNA binding site DNA binding sites are a type of binding site found in DNA where other molecules may bind. DNA binding sites are distinct from other binding sites in that (1) they are part of a DNA sequence (e.g. a genome) and (2) they are bound by DNA-binding ...
s 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 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 For molecular biology in mammals, DNA demethylation causes replacement of 5-methylcytosine (5mC) in a DNA sequence by cytosine (C) (see figure of 5mC and C). DNA demethylation can occur by an active process at the site of a 5mC in a DNA sequenc ...
). Multiple transcription factors important in cell differentiation and lineage specification, including NANOG, SALL4A,
WT1 Wilms tumor protein (WT33) is a protein that in humans is encoded by the ''WT1'' gene on chromosome 11p. Function This gene encodes a transcription factor that contains four zinc finger motifs at the C-terminus and a proline / glutamine-rich ...
, 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 the binding of 5mC-binding proteins including
MECP2 ''MECP2'' (methyl CpG binding protein 2) is a gene that encodes the protein MECP2. MECP2 appears to be essential for the normal function of nerve cells. The protein seems to be particularly important for mature nerve cells, where it is present in ...
and MBD (
Methyl-CpG-binding domain The Methyl-CpG-binding domain (MBD) in molecular biology binds to DNA that contains one or more symmetrically methylated CpGs. MBD has negligible non-specific affinity for unmethylated DNA. In vitro foot-printing with the chromosomal protein MeC ...
) proteins, facilitating nucleosome remodeling and the binding of transcription factors, thereby activating transcription of those genes.
EGR1 EGR-1 (Early growth response protein 1) also known as ZNF268 (zinc finger protein 268) or NGFI-A (nerve growth factor-induced protein A) is a protein that in humans is encoded by the ''EGR1'' gene. EGR-1 is a mammalian transcription factor. It wa ...
is an important transcription factor in
memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembered, ...
formation. It has an essential role in brain
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
epigenetic In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
reprogramming. The transcription factor
EGR1 EGR-1 (Early growth response protein 1) also known as ZNF268 (zinc finger protein 268) or NGFI-A (nerve growth factor-induced protein A) is a protein that in humans is encoded by the ''EGR1'' gene. EGR-1 is a mammalian transcription factor. It wa ...
recruits the TET1 protein that initiates a pathway of
DNA demethylation For molecular biology in mammals, DNA demethylation causes replacement of 5-methylcytosine (5mC) in a DNA sequence by cytosine (C) (see figure of 5mC and C). DNA demethylation can occur by an active process at the site of a 5mC in a DNA sequenc ...
. 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 While the cellular and molecular mechanisms of learning and memory have long been a central focus of neuroscience, it is only in recent years that attention has turned to the epigenetic mechanisms behind the dynamic changes in gene transcription r ...
).


Structure

Transcription factors are modular in structure and contain the following domains: *
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 genera ...
(DBD), which attaches to specific sequences of DNA ( enhancer or promoter. Necessary component for all vectors. Used to drive transcription of the vector's transgene promoter sequences) adjacent to regulated genes. DNA sequences that bind transcription factors are often referred to as
response elements Response elements are short sequences of DNA within a gene promoter or enhancer region that are able to bind specific transcription factors and regulate transcription of genes. Under conditions of stress, a transcription activator protein binds ...
. * Activation domain (AD), which contains binding sites for other proteins such as
transcription coregulator In molecular biology and genetics, transcription coregulators are proteins that interact with transcription factors to either activate or repress the transcription of specific genes. Transcription coregulators that activate gene transcription ar ...
s. These binding sites are frequently referred to as activation functions (AFs), Transactivation domain (TAD) or Trans-activating domain TAD but not mix with topologically associating domain TAD. * An optional signal-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.


DNA-binding domain

The portion (
domain Domain may refer to: Mathematics *Domain of a function, the set of input values for which the (total) function is defined ** Domain of definition of a partial function ** Natural domain of a partial function ** Domain of holomorphy of a function * ...
) 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:


Response elements

The DNA sequence that a transcription factor binds to is called a
transcription factor-binding site ''Cis''-regulatory elements (CREs) or ''Cis''-regulatory modules (CRMs) are regions of non-coding DNA which regulate the transcription of neighboring genes. CREs are vital components of genetic regulatory networks, which in turn control morphoge ...
or
response element Response elements are short sequences of DNA within a gene promoter or enhancer region that are able to bind specific transcription factors and regulate transcription of genes. Under conditions of stress, a transcription activator protein binds ...
. Transcription factors interact with their binding sites using a combination of
electrostatic Electrostatics is a branch of physics that studies electric charges at rest (static electricity). Since classical times, it has been known that some materials, such as amber, attract lightweight particles after rubbing. The Greek word for ambe ...
(of which
hydrogen bond In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...
s are a special case) and
Van der Waals force In molecular physics, the van der Waals force is a distance-dependent interaction between atoms or molecules. Unlike ionic or covalent bonds, these attractions do not result from a chemical electronic bond; they are comparatively weak and th ...
s. 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 do not 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 The TATA-binding protein (TBP) is a general transcription factor that binds specifically to a DNA sequence called the TATA box. This DNA sequence is found about 30 base pairs upstream of the transcription start site in some eukaryotic gene pr ...
(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 the DNA sequence is long enough. It is unlikely, however, that a transcription factor will bind all compatible sequences in the
genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding gen ...
of the
cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
. Other constraints, such as DNA accessibility in the cell or availability of
cofactors Cofactor may also refer to: * Cofactor (biochemistry), a substance that needs to be present in addition to an enzyme for a certain reaction to be catalysed * A domain parameter in elliptic curve cryptography, defined as the ratio between the order ...
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.


Clinical significance

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.


Disorders

Due to their important roles in development, intercellular signaling, and cell cycle, some human diseases have been associated with
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitos ...
s in transcription factors. Many transcription factors are either
tumor suppressor A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
s or
oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
s, 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) the NF-kappaB and AP-1 families, (2) the
STAT STAT, Stat. , or stat may refer to: * Stat (system call), a Unix system call that returns file attributes of an inode * ''Stat'' (TV series), an American sitcom that aired in 1991 * Stat (website), a health-oriented news website * STAT protein, a ...
family and (3) the steroid receptors. Below are a few of the better-studied examples:


Potential drug targets

Approximately 10% of currently prescribed drugs directly target the
nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of spec ...
class of transcription factors. Examples include
tamoxifen Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men. It is also being studied for other types of cancer. It has ...
and
bicalutamide Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer. It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical remo ...
for the treatment of
breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and secret ...
and
prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...
, respectively, and various types of
anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as op ...
and
anabolic Anabolism () is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breaking-d ...
steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...
s. 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 Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
with drugs. Transcription factors outside the nuclear receptor family are thought to be more difficult to target with
small molecule Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs are ...
therapeutics since it is not clear that they are "drugable" but progress has been made on Pax2 and the notch pathway. *


Role in evolution

Gene duplications have played a crucial role in the
evolution Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
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-copy
Leafy LEAFY (abbreviated LFY) is a plant gene that causes groups of undifferentiated cells called meristems to develop into flowers instead of leaves with associated shoots. ''LEAFY'' is involved in floral meristem identity. ''LEAFY'' encodes a plant ...
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 In biology, phylogenetics (; from Greek φυλή/ φῦλον [] "tribe, clan, race", and wikt:γενετικός, γενετικός [] "origin, source, birth") is the study of the evolutionary history and relationships among or within groups o ...
hypotheses, and the role of transcription factors in the evolution of all species.


Role in biocontrol activity

The transcription factors have a role in resistance activity which important for successful
biocontrol Biological control or biocontrol is a method of controlling pests, such as insects, mites, weeds, and plant diseases, using other organisms. It relies on predation, parasitism, herbivory, or other natural mechanisms, but typically also invo ...
activity. The resistant to
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal r ...
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 will supports disease management programs based on biological and integrated control.


Analysis

There are different technologies available to analyze transcription factors. On the
genomic Genomics is an interdisciplinary field of biology focusing on the structure, function, evolution, mapping, and editing of genomes. A genome is an organism's complete set of DNA, including all of its genes as well as its hierarchical, three-dim ...
level, DNA-
sequencing In genetics and biochemistry, sequencing means to determine the primary structure (sometimes incorrectly called the primary sequence) of an unbranched biopolymer. Sequencing results in a symbolic linear depiction known as a sequence which succi ...
and database research are commonly used. The protein version of the transcription factor is detectable by using specific
antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
. The sample is detected on a
western blot The western blot (sometimes called the protein immunoblot), or western blotting, is a widely used analytical technique in molecular biology and immunogenetics to detect specific proteins in a sample of tissue homogenate or extract. Besides detecti ...
. By using
electrophoretic mobility shift assay An electrophoretic mobility shift assay (EMSA) or mobility shift electrophoresis, also referred as a gel shift assay, gel mobility shift assay, band shift assay, or gel retardation assay, is a common affinity electrophoresis technique used to stu ...
(EMSA), the activation profile of transcription factors can be detected. A
multiplex Multiplex may refer to: * Multiplex (automobile), a former American car make * Multiplex (comics), a DC comic book supervillain * Multiplex (company), a global contracting and development company * Multiplex (assay), a biological assay which measu ...
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 is
chromatin immunoprecipitation Chromatin immunoprecipitation (ChIP) is a type of immunoprecipitation experimental technique used to investigate the interaction between proteins and DNA in the cell. It aims to determine whether specific proteins are associated with specific genom ...
(ChIP). This technique relies on chemical fixation of chromatin with
formaldehyde Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section Fo ...
, followed by co-precipitation of DNA and the transcription factor of interest using an
antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
that specifically targets that protein. The DNA sequences can then be identified by microarray or high-throughput sequencing (
ChIP-seq ChIP-sequencing, also known as ChIP-seq, is a method used to analyze protein interactions with DNA. ChIP-seq combines chromatin immunoprecipitation (ChIP) with massively parallel DNA sequencing to identify the binding sites of DNA-associated prot ...
) to determine transcription factor binding sites. If no antibody is available for the protein of interest,
DamID DNA adenine methyltransferase identification, often abbreviated DamID, is a molecular biology protocol used to map the binding sites of DNA- and chromatin-binding proteins in eukaryotes. DamID identifies binding sites by expressing the proposed D ...
may be a convenient alternative.


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.


Mechanistic

There are two mechanistic classes of transcription factors: *
General transcription factor General transcription factors (GTFs), also known as basal transcriptional factors, are a class of protein transcription factors that bind to specific sites ( promoter) on DNA to activate transcription of genetic information from DNA to messenger ...
s are involved in the formation of a preinitiation complex. The most common are abbreviated as
TFIIA Transcription factor TFIIA is a nuclear protein involved in the RNA polymerase II-dependent transcription of DNA. TFIIA is one of several general (basal) transcription factors (GTFs) that are required for all transcription events that use RNA p ...
,
TFIIB Transcription factor II B (TFIIB) is a general transcription factor that is involved in the formation of the RNA polymerase II preinitiation complex (PIC) and aids in stimulating transcription initiation. TFIIB is localised to the nucleus and pro ...
,
TFIID Transcription factor II D (TFIID) is one of several general transcription factors that make up the RNA polymerase II preinitiation complex. RNA polymerase II holoenzyme is a form of eukaryotic RNA polymerase II that is recruited to the promoters ...
,
TFIIE Transcription factor II E (TFIIE) is one of several general transcription factors that make up the RNA polymerase II preinitiation complex. It is a tetramer of two alpha and two beta chains and interacts with TAF6/TAFII80, ATF7IP, and varicella ...
,
TFIIF Transcription factor II F (TFIIF) is one of several general transcription factors that make up the RNA polymerase II preinitiation complex. TFIIF is encoded by the , , and genes. TFIIF binds to RNA polymerase II RNA polymerase II (RNAP II ...
, and
TFIIH Transcription factor II Human (transcription factor II H; TFIIH) is an important protein complex, having roles in transcription of various protein-coding genes and DNA nucleotide excision repair (NER) pathways. TFIIH first came to light in 1989 ...
. They are ubiquitous and interact with the core promoter region surrounding the transcription start site(s) of all class II genes. *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 A recognition sequence is a DNA sequence to which a structural motif of a DNA-binding domain exhibits binding specificity. Recognition sequences are palindromes. The transcription factor Sp1 for example, binds the sequences 5'-(G/T)GGGCGG(G/A)(G ...
s are present in the proximity of the gene.


Functional

Transcription factors have been classified according to their regulatory function: * I. constitutively active – present in all cells at all times –
general transcription factor General transcription factors (GTFs), also known as basal transcriptional factors, are a class of protein transcription factors that bind to specific sites ( promoter) on DNA to activate transcription of genetic information from DNA to messenger ...
s, 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 Davionte Ganter, known professionally as GaTa, is an American rapper and actor known for his role in the FXX TV series ''Dave'', as well as for being the hype man for rapper Lil Dicky throughout his career as well as on the show. Early life an ...
, HNF, PIT-1,
MyoD MyoD, also known as myoblast determination protein 1, is a protein in animals that plays a major role in regulating muscle differentiation. MyoD, which was discovered in the laboratory of Harold M. Weintraub, belongs to a family of proteins kno ...
, Myf5, Hox, Winged Helix ** II.B signal-dependent – requires external signal for activation *** II.B.1 extracellular ligand (
endocrine The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neur ...
or
paracrine Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse ove ...
)-dependent –
nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of spec ...
s *** II.B.2 intracellular ligand (
autocrine Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with pa ...
)-dependent – activated by small intracellular molecules –
SREBP Sterol regulatory element-binding proteins (SREBPs) are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes '' SREBF1'' and '' SREBF2''. SREBPs belong to the basic ...
,
p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often ...
, 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 CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first des ...
, AP-1,
Mef2 In the field of molecular biology, myocyte enhancer factor-2 (Mef2) proteins are a family of transcription factors which through control of gene expression are important regulators of cellular differentiation and consequently play a critical ro ...
**** II.B.3.b latent cytoplasmic factors – inactive form reside in the cytoplasm, but, when activated, are translocated into the nucleus –
STAT STAT, Stat. , or stat may refer to: * Stat (system call), a Unix system call that returns file attributes of an inode * ''Stat'' (TV series), an American sitcom that aired in 1991 * Stat (website), a health-oriented news website * STAT protein, a ...
,
R-SMAD R-SMADs are receptor-regulated SMADs. SMADs are transcription factors that transduce extracellular TGF-β superfamily ligand signaling from cell membrane bound TGF-β receptors into the nucleus where they activate transcription TGF-β target ge ...
,
NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
, Notch,
TUBBY Tubby is a nickname and surname and may refer to: People Nickname * Tubby Clayton (1885–1972), Anglican clergyman, founder of the Christian movement Toc H * Michael Lindsay Coulton Crawford (1917–2017), Second World War Royal Navy officer an ...
,
NFAT Nuclear factor of activated T-cells (NFAT) is a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the developme ...


Structural

Transcription factors are often classified based on the
sequence similarity Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...
and hence the
tertiary structure Protein tertiary structure is the three dimensional shape of a protein. The tertiary structure will have a single polypeptide chain "backbone" with one or more protein secondary structures, the protein domains. Amino acid side chains may inte ...
of their DNA-binding domains: *1 Superclass: Basic Domains **1.1 Class:
Leucine zipper A leucine zipper (or leucine scissors) is a common three-dimensional structural motif in proteins. They were first described by Landschulz and collaborators in 1988 when they found that an enhancer binding protein had a very characteristic 30-am ...
factors (
bZIP The Basic Leucine Zipper Domain (bZIP domain) is found in many DNA binding eukaryotic proteins. One part of the domain contains a region that mediates sequence specific DNA binding properties and the leucine zipper that is required to hold tog ...
) ***1.1.1 Family: AP-1(-like) components; includes (
c-Fos Protein c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos. It is encoded in humans by the ''FOS'' gene. It was first discovered in rat fibroblasts as the transforming gene of the FBJ MSV (Finkel–Biskis–Jinkin ...
/
c-Jun Transcription factor Jun is a protein that in humans is encoded by the ''JUN'' gene. c-Jun, in combination with protein c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only l ...
) ***1.1.2 Family:
CREB CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first des ...
***1.1.3 Family:
C/EBP CCAAT-enhancer-binding proteins (or C/EBPs) is a family of transcription factors composed of six members, named from C/EBPα to C/EBPζ. They promote the expression of certain genes through interaction with their promoters. Once bound to DNA, C ...
-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 MyoD, also known as myoblast determination protein 1, is a protein in animals that plays a major role in regulating muscle differentiation. MyoD, which was discovered in the laboratory of Harold M. Weintraub, belongs to a family of proteins kno ...
) ***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 Upstream stimulatory factor 1 is a protein that in humans is encoded by the ''USF1'' gene. Function This gene encodes a member of the basic helix-loop-helix leucine zipper family and can function as a cellular transcription factor. The enco ...
,
USF2 Upstream stimulatory factor 2 is a protein that in humans is encoded by the ''USF2'' gene. Function This gene encodes a member of the basic helix-loop-helix leucine zipper family, and can function as a cellular transcription factor. The encod ...
); SREBP (
SREBP Sterol regulatory element-binding proteins (SREBPs) are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes '' SREBF1'' and '' SREBF2''. SREBPs belong to the basic ...
) ***1.3.2 Family: Cell-cycle controlling factors; includes
c-Myc ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' (MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes referre ...
**1.4 Class: NF-1 ***1.4.1 Family: NF-1 ( A, B, C, X) **1.5 Class: RF-X ***1.5.1 Family: RF-X ( 1, 2, 3, 4, 5, ANK) **1.6 Class: bHSH *2 Superclass: Zinc-coordinating DNA-binding domains **2.1 Class: Cys4
zinc finger A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) in order to stabilize the fold. It was originally coined to describe the finger-like appearance of a hypothesized struct ...
of
nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of spec ...
type ***2.1.1 Family:
Steroid hormone receptor Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors (typically cytoplasmic or nuclear) and initiate signal transduction for steroid hormones which ...
s ***2.1.2 Family:
Thyroid hormone receptor The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. TRs act as transcription factors, ultimately affecting the regulation of gene transcription and translation. These receptors also have ...
-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 Krüppel is a gap gene in ''Drosophila melanogaster'', located on the 2R chromosome, which encodes a zinc finger C2H2 transcription factor. Gap genes work together to establish the anterior-posterior segment patterning of the insect through r ...
***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 Helix-turn-helix is a DNA-binding protein (DBP). The helix-turn-helix (HTH) is a major structural motif capable of binding DNA. Each monomer incorporates two α helices, joined by a short strand of amino acids, that bind to the major groove of ...
**3.1 Class: Homeo domain ***3.1.1 Family: Homeo domain only; includes Ubx ***3.1.2 Family:
POU domain POU (pronounced 'pow') is a family of proteins that have well-conserved homeodomains. Etymology The acronym POU is derived from the names of three transcription factors: * the Pituitary-specific Pit-1 * the Octamer transcription factor prote ...
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 FOX (forkhead box) proteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity. Many FOX proteins are important to embryonic ...
***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 Interferon regulatory factors (IRF) are proteins which regulate transcription of interferons (see regulation of gene expression). Interferon regulatory factors contain a conserved N-terminal region of about 120 amino acids, which folds into a st ...
**3.6 Class: TEA ( transcriptional enhancer factor) domain ***3.6.1 Family: TEA (
TEAD1 Transcriptional enhancer factor TEF-1 also known as TEA domain family member 1 (TEAD1) and transcription factor 13 (TCF-13) is a protein that in humans is encoded by the ''TEAD1'' gene. TEAD1 was the first member of the TEAD family of transcriptio ...
,
TEAD2 TEAD2 (ETF, ETEF-1, TEF-4), together with TEAD1, defines a novel family of transcription factors, the TEAD family, highly conserved through evolution. TEAD proteins were notably found in ''Drosophila'' (Scalloped), '' C. elegans'' (egl -44), '' ...
,
TEAD3 Transcriptional enhancer factor TEF-5 is a protein that in humans is encoded by the ''TEAD3'' gene. Function This gene product is a member of the transcriptional enhancer factor (TEF) family of transcription factors, which contain the TEA/ATT ...
,
TEAD4 Transcriptional enhancer factor TEF-3 is a protein that in humans is encoded by the ''TEAD4'' gene. Function This gene product is a member of the transcriptional enhancer factor (TEF) family of transcription factors, which contain the TEA/ATT ...
) *4 Superclass: beta-Scaffold Factors with Minor Groove Contacts **4.1 Class: RHR ( Rel homology region) ***4.1.1 Family: Rel/
ankyrin Ankyrins are a family of proteins that mediate the attachment of integral membrane proteins to the spectrin-actin based membrane cytoskeleton. Ankyrins have binding sites for the beta subunit of spectrin and at least 12 families of integral mem ...
; NF-kappaB ***4.1.2 Family: ankyrin only ***4.1.3 Family:
NFAT Nuclear factor of activated T-cells (NFAT) is a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the developme ...
(Nuclear Factor of Activated T-cells) (
NFATC1 Nuclear factor of activated T-cells, cytoplasmic 1 is a protein that in humans is encoded by the ''NFATC1'' gene. Function The product of this gene is a component of the nuclear factor of activated T cells DNA-binding transcription complex. T ...
,
NFATC2 Nuclear factor of activated T-cells, cytoplasmic 2 is a protein that in humans is encoded by the ''NFATC2'' gene. Function This gene is a member of the nuclear factor of activated T cells (NFAT) family. The product of this gene is a DNA-bindi ...
,
NFATC3 Nuclear factor of activated T-cells, cytoplasmic 3 is a protein that in humans is encoded by the ''NFATC3'' gene. Function The product of this gene is a member of the nuclear factors of activated T cells DNA-binding transcription complex. Thi ...
) **4.2 Class: STAT ***4.2.1 Family:
STAT STAT, Stat. , or stat may refer to: * Stat (system call), a Unix system call that returns file attributes of an inode * ''Stat'' (TV series), an American sitcom that aired in 1991 * Stat (website), a health-oriented news website * STAT protein, a ...
**4.3 Class: p53 ***4.3.1 Family:
p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often ...
**4.4 Class: MADS box ***4.4.1 Family: Regulators of differentiation; includes (
Mef2 In the field of molecular biology, myocyte enhancer factor-2 (Mef2) proteins are a family of transcription factors which through control of gene expression are important regulators of cellular differentiation and consequently play a critical ro ...
) ***4.4.2 Family: Responders to external signals, SRF (
serum response factor Serum response factor, also known as SRF, is a transcription factor protein. Function Serum response factor is a member of the MADS (MCM1, Agamous, Deficiens, and SRF) box superfamily of transcription factors. This protein binds to the serum ...
) () ***4.4.3 Family: Metabolic regulators (ARG80) **4.5 Class: beta-Barrel alpha-helix transcription factors **4.6 Class:
TATA binding protein The TATA-binding protein (TBP) is a general transcription factor that binds specifically to a DNA sequence called the TATA box. This DNA sequence is found about 30 base pairs upstream of the transcription start site in some eukaryotic gene p ...
s ***4.6.1 Family: TBP **4.7 Class:
HMG-box In molecular biology, the HMG-box (high mobility group box) is a protein domain which is involved in DNA binding. Structure The structure of the HMG-box domain contains three alpha helices separated by loops (see figure to the right). Function ...
***4.7.1 Family:
SOX genes ''SOX'' genes ('' SRY''-related HMG-box genes) encode a family of transcription factors that bind to the minor groove in DNA, and belong to a super-family of genes characterized by a homologous sequence called the HMG-box (for high mobility g ...
, SRY ***4.7.2 Family: TCF-1 ( TCF1) ***4.7.3 Family: HMG2-related, 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: AP2 ***0.5.2 Family: EREBP ***0.5.3 Superfamily: AP2/B3 ****0.5.3.1 Family: ARF ****0.5.3.2 Family: ABI ****0.5.3.3 Family: RAV


See also

*
Cdx protein family The Cdx protein family is a group of the transcription factor proteins which bind to DNA to regulate the expression of genes. In particular this family of proteins can regulate the Hox genes. They are regulators of embryonic development and hematop ...
*
DNA-binding protein DNA-binding proteins are proteins that have DNA-binding domains and thus have a specific or general affinity for single- or double-stranded DNA. Sequence-specific DNA-binding proteins generally interact with the major groove of B-DNA, beca ...
* Inhibitor of DNA-binding protein * Mapper(2) *
Nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of spec ...
, a class of ligand activated transcription factors *
Open Regulatory Annotation Database The Open Regulatory Annotation Database (also known as ORegAnno) is designed to promote community-based curation of regulatory information. Specifically, the database contains information about regulatory regions, transcription factor binding site ...
* Phylogenetic footprinting * TRANSFAC database * YeTFaSCo


References


Further reading

* 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
* *


External links

*
Transcription factor database

Plant Transcription Factor Database and Transcriptional Regulation Data and Analysis Platform
{{Authority control Gene expression Protein families DNA Biophysics Evolutionary developmental biology