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 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
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 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. – Many transcription factors such as
STAT proteins must be
phosphorylated before they can bind DNA. • interaction with other transcription factors (
e.g., homo- or hetero-
dimerization) • interacting with
coregulatory proteins such as co-activators (e.g.,
COPS5,
EP300,
BCL3); co-repressors (e.g.,
NCOR1,
SIN3A,
TRIM24). However, there are
transcription co-regulators that can act as both, activator and repressors.
Accessibility of DNA-binding site In eukaryotes, DNA 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, 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.
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 that allow efficient recruitment of 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 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.
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.) 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 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 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,
SALL4A,
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 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 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). == Structure ==