Transcriptional regulation

It is orchestrated by transcription factors and other proteins working in concert to finely tune the amount of RNA being produced through a variety of mechanisms.

Bacteria and eukaryotes have very different strategies of accomplishing control over transcription, but some important features remain conserved between the two.

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.

[8] Sigma factors are specialized bacterial proteins that bind to RNA polymerases and orchestrate transcription initiation.

[10] RNA polymerase pauses occur frequently and are regulated by transcription factors, such as NusG and NusA, transcription-translation coupling, and mRNA secondary structure.

These mechanisms can be generally grouped into three main areas: All three of these systems work in concert to integrate signals from the cell and change the transcriptional program accordingly.

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.

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.

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.

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.

This is accomplished by winding the DNA around protein octamers called histones, which has consequences for the physical accessibility of parts of the genome at any given time.

[20] Transcription factors are proteins that bind to specific DNA sequences in order to regulate the expression of a gene.

[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.

[30] Transcription factors are proteins that bind to specific DNA sequences in order to regulate the expression of a given gene.

[21] The power of transcription factors resides in their ability to activate and/or repress wide repertoires of downstream target genes.

Post-translational modifications to transcription factors located in the cytosol can cause them to translocate to the nucleus where they can interact with their corresponding enhancers.

Some post-translational modifications known to regulate the functional state of transcription factors are phosphorylation, acetylation, SUMOylation and ubiquitylation.

[37] Among this constellation of sequences, enhancers and their associated transcription factor proteins have a leading role in the regulation of gene expression.

[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.

[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.

[46] Chromosome conformation capture (3C) and more recently Hi-C techniques provided evidence that active chromatin regions are “compacted” in nuclear domains or bodies where transcriptional regulation is enhanced.

Cell-fate decisions are mediated upon highly dynamic genomic reorganizations at interphase to modularly switch on or off entire gene regulatory networks through short to long range chromatin rearrangements.

TAD boundaries are often composed by housekeeping genes, tRNAs, other highly expressed sequences and Short Interspersed Elements (SINE).

The specific molecules identified at boundaries of TADs are called insulators or architectural proteins because they not only block enhancer leaky expression but also ensure an accurate compartmentalization of cis-regulatory inputs to the targeted promoter.

Particularly for Pol II, much of the regulatory checkpoints in the transcription process occur in the assembly and escape of the pre-initiation complex.

This assembly is marked by the post-translational modification (typically phosphorylation) of the C-terminal domain (CTD) of Pol II through a number of kinases.

[55] The CTD is a large, unstructured domain extending from the RbpI subunit of Pol II, and consists of many repeats of the heptad sequence YSPTSPS.

TFIIH, the helicase that remains associated with Pol II throughout transcription, also contains a subunit with kinase activity which will phosphorylate the serines 5 in the heptad sequence.

The maltose operon is an example of a positive control of transcription. [ 1 ] When maltose is not present in E. coli, no transcription of the maltose genes will occur, and there is no maltose to bind to the maltose activator protein. This prevents the activator protein from binding to the activator binding site on the gene, which in turn prevents RNA polymerase from binding to the maltose promoter. No transcription takes place. [ 1 ]
When maltose is present in E. coli, it binds to the maltose activator protein (#1), which promotes maltose activator protein binding to the activator binding site (#2). This allows the RNA polymerase to bind to the mal promoter (#3). Transcription of malE, malF, and malG genes then proceeds (#4) as maltose activator protein and RNA polymerase moves down the DNA. [ 1 ] malE encodes for maltose-binding periplasmic protein and helps maltose transport across the cell membrane. [ 5 ] malF encodes for maltose transport system permease protein and helps translocate maltose across the cell membrane. [ 6 ] malG encodes for transport system protein and also helps translocate maltose across the cell membrane. [ 7 ]
Schematic karyogram of a human , showing an overview of the human genome on G banding , which is a method that includes Giemsa staining , wherein the lighter staining regions are generally more transcriptionally active, whereas darker regions are more inactive.
Further information: Karyotype
DNA methylation is the addition of a methyl group to the DNA that happens at cytosine . The image shows a cytosine single ring base and a methyl group added on to the 5 carbon. In mammals, DNA methylation occurs almost exclusively at a cytosine that is followed by a guanine .
Enhance function in regulation of transcription in mammals . An active enhancer regulatory sequence of DNA is enabled to interact with the promoter DNA regulatory sequence of its target gene by formation of a chromosome loop. This can initiate messenger RNA (mRNA) synthesis by RNA polymerase II (RNAP II) bound to the promoter at the transcription start site of the gene. The loop is stabilized by one architectural protein anchored to the enhancer and one anchored to the promoter and these proteins are joined to form a dimer (red zigzags). Specific regulatory transcription factors bind to DNA sequence motifs on the enhancer. General transcription factors bind to the promoter. When a transcription factor is activated by a signal (here indicated as phosphorylation shown by a small red star on a transcription factor on the enhancer) the enhancer is activated and can now activate its target promoter. The active enhancer is transcribed on each strand of DNA in opposite directions by bound RNAP IIs. Mediator (a complex consisting of about 26 proteins in an interacting structure) communicates regulatory signals from the enhancer DNA-bound transcription factors to the promoter.