Transcriptional regulation
Transcription regulation glossary
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• transcriptional regulation – controlling the rate of gene transcription for example by helping or hindering RNA polymerase binding to DNA |
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• transcription factor – a substance, such as a protein, that contributes to the cause of a specific biochemical reaction or bodily process |
• promoter – a region of DNA that initiates transcription of a particular gene |
• Sigma factor – specialized bacterial co-factors that complex with RNA Polymerase and encode sequence specificity |
• coactivator – a protein that works with transcription factors to increase the rate of gene transcription |
• corepressor – a protein that works with transcription factors to decrease the rate of gene transcription
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In
The regulation of transcription is a vital process in all living organisms. It is orchestrated by
In bacteria
Much of the early understanding of transcription came from bacteria,[2] although the extent and complexity of transcriptional regulation is greater in eukaryotes. Bacterial transcription is governed by three main sequence elements:
- Promoters are elements of DNA that may bind RNA polymerase and other proteins for the successful initiation of transcription directly upstream of the gene.
- Operators recognize repressor proteins that bind to a stretch of DNA and inhibit the transcription of the gene.
- Positive control elements that bind to DNA and incite higher levels of transcription.[3]
While these means of transcriptional regulation also exist in eukaryotes, the transcriptional landscape is significantly more complicated both by the number of proteins involved as well as by the presence of
The transcription of a basic bacterial gene is dependent on the strength of its promoter and the presence of activators or repressors. In the absence of other regulatory elements, a promoter's sequence-based affinity for RNA polymerases varies, which results in the production of different amounts of transcript. The variable affinity of RNA polymerase for different promoter sequences is related to regions of consensus sequence upstream of the transcription start site. The more nucleotides of a promoter that agree with the consensus sequence, the stronger the affinity of the promoter for RNA Polymerase likely is.[4]
In the absence of other regulatory elements, the default state of a bacterial transcript is to be in the “on” configuration, resulting in the production of some amount of transcript. This means that transcriptional regulation in the form of protein repressors and positive control elements can either increase or decrease transcription. Repressors often physically occupy the promoter location, occluding RNA polymerase from binding. Alternatively a repressor and polymerase may bind to the DNA at the same time with a physical interaction between the repressor preventing the opening of the DNA for access to the minus strand for transcription. This strategy of control is distinct from eukaryotic transcription, whose basal state is to be off and where co-factors required for transcription initiation are highly gene dependent.[8]
Sigma factors are specialized bacterial proteins that bind to RNA polymerases and orchestrate transcription initiation. Sigma factors act as mediators of sequence-specific transcription, such that a single sigma factor can be used for transcription of all housekeeping genes or a suite of genes the cell wishes to express in response to some external stimuli such as stress.[9]
In addition to processes that regulate transcription at the stage of initiation, mRNA synthesis is also controlled by the rate of transcription elongation.[10] RNA polymerase pauses occur frequently and are regulated by transcription factors, such as NusG and NusA, transcription-translation coupling, and mRNA secondary structure.[11][12]
In eukaryotes
The added complexity of generating a eukaryotic cell carries with it an increase in the complexity of transcriptional regulation. Eukaryotes have three RNA polymerases, known as
- Control over polymerase access to the gene. This is perhaps the broadest of the three control mechanisms. This includes the functions of histone remodeling enzymes, transcription factors, enhancers and repressors, and many other complexes
- Productive elongation of the RNA transcript. Once polymerase is bound to a promoter, it requires another set of factors to allow it to escape the promoter complex and begin successfully transcribing RNA.
- Termination of the polymerase. A number of factors which have been found to control how and when termination occurs, which will dictate the fate of the RNA transcript.
All three of these systems work in concert to integrate signals from the cell and change the transcriptional program accordingly.
While in prokaryotic systems the basal transcription state can be thought of as nonrestrictive (that is, “on” in the absence of modifying factors), eukaryotes have a restrictive basal state which requires the recruitment of other factors in order to generate RNA transcripts. This difference is largely due to the compaction of the eukaryotic genome by winding DNA around histones to form higher order structures. This compaction makes the gene promoter inaccessible without the assistance of other factors in the nucleus, and thus chromatin structure is a common site of regulation. Similar to the sigma factors in prokaryotes, the general transcription factors (GTFs) are a set of factors in eukaryotes that are required for all transcription events. These factors are responsible for stabilizing binding interactions and opening the DNA helix to allow the RNA polymerase to access the template, but generally lack specificity for different promoter sites.[13] A large part of gene regulation occurs through transcription factors that either recruit or inhibit the binding of the general transcription machinery and/or the polymerase. This can be accomplished through close interactions with core promoter elements, or through the long distance enhancer elements.
Once a polymerase is successfully bound to a DNA template, it often requires the assistance of other proteins in order to leave the stable promoter complex and begin elongating the nascent RNA strand. This process is called promoter escape, and is another step at which regulatory elements can act to accelerate or slow the transcription process. Similarly, protein and nucleic acid factors can associate with the elongation complex and modulate the rate at which the polymerase moves along the DNA template.
At the level of chromatin state
In eukaryotes, genomic DNA is highly compacted in order to be able to fit it into the nucleus. This is accomplished by winding the DNA around protein octamers called
Histone rearrangement is facilitated by
At the level of cytosine methylation
Transcription regulation at about 60% of
DNA methylation regulates gene transcription through interaction with
EGR1 protein is a particular transcription factor that is important for regulation of methylation of CpG islands. An EGR1 transcription factor binding site is frequently located in enhancer or promoter sequences.[23] There are about 12,000 binding sites for EGR1 in the mammalian genome and about half of EGR1 binding sites are located in promoters and half in enhancers.[23] The binding of EGR1 to its target DNA binding site is insensitive to cytosine methylation in the DNA.[23]
While only small amounts of EGR1 transcription factor protein are detectable in cells that are un-stimulated, translation of the EGR1 gene into protein at one hour after stimulation is drastically elevated.[24] Expression of EGR1 transcription factor proteins, in various types of cells, can be stimulated by growth factors, neurotransmitters, hormones, stress and injury.[24] In the brain, when neurons are activated, EGR1 proteins are up-regulated and they bind to (recruit) the pre-existing TET1 enzymes which are highly expressed in neurons. TET enzymes can catalyse demethylation of 5-methylcytosine. When EGR1 transcription factors bring TET1 enzymes to EGR1 binding sites in promoters, the TET enzymes can demethylate the methylated CpG islands at those promoters. Upon demethylation, these promoters can then initiate transcription of their target genes. Hundreds of genes in neurons are differentially expressed after neuron activation through EGR1 recruitment of TET1 to methylated regulatory sequences in their promoters.[23]
The methylation of promoters is also altered in response to signals. The three mammalian DNA methyltransferasess (DNMT1, DNMT3A, and DNMT3B) catalyze the addition of methyl groups to cytosines in DNA. While DNMT1 is a “maintenance” methyltransferase, DNMT3A and DNMT3B can carry out new methylations. There are also two splice protein isoforms produced from the DNMT3A gene: DNA methyltransferase proteins DNMT3A1 and DNMT3A2.[25]
The splice isoform DNMT3A2 behaves like the product of a classical immediate-early gene and, for instance, it is robustly and transiently produced after neuronal activation.[26] Where the DNA methyltransferase isoform DNMT3A2 binds and adds methyl groups to cytosines appears to be determined by histone post translational modifications.[27][28][29]
On the other hand, neural activation causes degradation of DNMT3A1 accompanied by reduced methylation of at least one evaluated targeted promoter.[30]
Through transcription factors and enhancers
Transcription factors
Enhancers
Enhancers or cis-regulatory modules/elements (CRM/CRE) are non-coding DNA sequences containing multiple activator and repressor binding sites. Enhancers range from 200 bp to 1 kb in length and can be either proximal, 5’ upstream to the promoter or within the first intron of the regulated gene, or distal, in introns of neighboring genes or intergenic regions far away from the locus. Through DNA looping, active enhancers contact the promoter dependently of the core DNA binding motif promoter specificity.[34] Promoter-enhancer dichotomy provides the basis for the functional interaction between transcription factors and transcriptional core machinery to trigger RNA Pol II escape from the promoter. Whereas one could think that there is a 1:1 enhancer-promoter ratio, studies of the human genome predict that an active promoter interacts with 4 to 5 enhancers. Similarly, enhancers can regulate more than one gene without linkage restriction and are said to “skip” neighboring genes to regulate more distant ones. Even though infrequent, transcriptional regulation can involve elements located in a chromosome different from one where the promoter resides. Proximal enhancers or promoters of neighboring genes can serve as platforms to recruit more distal elements.[35]
Enhancer activation and implementation
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Up-regulated expression of genes in mammals can be initiated when signals are transmitted to the promoters associated with the genes.
Enhancers are sequences of the genome that are major gene-regulatory elements. Enhancers control cell-type-specific gene expression programs, most often by looping through long distances to come in physical proximity with the promoters of their target genes.[39] In a study of brain cortical neurons, 24,937 loops were found, bringing enhancers to promoters.[36] Multiple enhancers, each often at tens or hundred of thousands of nucleotides distant from their target genes, loop to their target gene promoters and coordinate with each other to control expression of their common target gene.[39]
The schematic illustration in this section shows an enhancer looping around to come into close physical proximity with the promoter of a target gene. The loop is stabilized by a dimer of a connector protein (e.g. dimer of CTCF or YY1), with one member of the dimer anchored to its binding motif on the enhancer and the other member anchored to its binding motif on the promoter (represented by the red zigzags in the illustration).[40] Several cell function specific transcription factor proteins (in 2018 Lambert et al. indicated there were about 1,600 transcription factors in a human cell[41]) generally bind to specific motifs on an enhancer[22] and a small combination of these enhancer-bound transcription factors, when brought close to a promoter by a DNA loop, govern the level of transcription of the target gene. Mediator (coactivator) (a complex usually consisting of about 26 proteins in an interacting structure) communicates regulatory signals from enhancer DNA-bound transcription factors directly to the RNA polymerase II (RNAP II) enzyme bound to the promoter.[42]
Enhancers, when active, are generally transcribed from both strands of DNA with RNA polymerases acting in two different directions, producing two eRNAs as illustrated in the Figure.[43] An inactive enhancer may be bound by an inactive transcription factor. Phosphorylation of the transcription factor may activate it and that activated transcription factor may then activate the enhancer to which it is bound (see small red star representing phosphorylation of a transcription factor bound to an enhancer in the illustration).[44] An activated enhancer begins transcription of its RNA before activating a promoter to initiate transcription of messenger RNA from its target gene.[45]
Regulatory landscape
Transcriptional initiation, termination and regulation are mediated by “DNA looping” which brings together promoters, enhancers, transcription factors and RNA processing factors to accurately regulate gene expression.
Of the pre-initiation complex and promoter escape
In eukaryotes,
In cancer
In vertebrates, the majority of gene promoters contain a CpG island with numerous CpG sites.[57] When many of a gene's promoter CpG sites are methylated the gene becomes silenced.[58] Colorectal cancers typically have 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations.[59] However, transcriptional silencing may be of more importance than mutation in causing progression to cancer. For example, in colorectal cancers about 600 to 800 genes are transcriptionally silenced by CpG island methylation (see regulation of transcription in cancer). Transcriptional repression in cancer can also occur by other epigenetic mechanisms, such as altered expression of microRNAs.[60] In breast cancer, transcriptional repression of BRCA1 may occur more frequently by over-expressed microRNA-182 than by hypermethylation of the BRCA1 promoter (see Low expression of BRCA1 in breast and ovarian cancers).
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