In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from altering the number of copies of RNA that are transcribed, to the temporal control of when the gene is transcribed. This control allows the cell or organism to respond to a variety of intra- and extracellular signals and thus mount a response.
Examples of this include producing the mRNA that encode enzymes to adapt to a change in a food source, producing the gene products involved in cell cycle specific activities, and producing the gene products responsible for cellular differentiation in multicellular eukaryotes, as studied in evolutionary developmental biology.
The regulation of transcription is a vital process in all living organisms. 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.
Prokaryotic organisms and eukaryotic organisms have very different strategies of accomplishing control over transcription, but some important features remain conserved between the two.
Most importantly is the idea of combinatorial control, which is that any given gene is likely controlled by a specific combination of factors to control transcription. In a hypothetical example, the factors A and B might regulate a distinct set of genes from the combination of factors A and C. This combinatorial nature extends to complexes of far more than two proteins, and allows a very small subset (less than 10%) of the genome to control the transcriptional program of the entire cell.
Much of the early understanding of transcription came from prokaryotic organisms, although the extent and complexity of transcriptional regulation is greater in eukaryotes. Prokaryotic 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.
The complexity of generating a eukaryotic cell carries with it an increase in the complexity of transcriptional regulation, much more complex than with a prokaryote.
Eukaryotes have three RNA polymerases, known as Pol I, Pol II, and Pol III. Each polymerase has specific targets and activities, and is regulated by independent mechanisms. There are a number of additional mechanisms through which polymerase activity can be controlled. These mechanisms can be generally grouped into three main areas:
- 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.
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 histones, which has consequences for the physical accessibility of parts of the genome at any given time. Significant portions are silenced through histone modifications, and thus are inaccessible to the polymerases or their cofactors.
The highest level of transcription regulation occurs through the rearrangement of histones in order to expose or sequester genes, because these processes have the ability to render entire regions of a chromosome inaccessible such as what occurs in imprinting.
Histone rearrangement is facilitated by post-translational modifications to the tails of the core histones. A wide variety of modifications can be made by enzymes such as the histone acetyltransferases (HATs), histone methyltransferases (HMTs), and histone deacetylases (HDACs), among others.
These enzymes can add or remove covalent modifications such as methyl groups, acetyl groups, phosphates, and ubiquitin. Histone modifications serve to recruit other proteins which can either increase the compaction of the chromatin and sequester promoter elements, or to increase the spacing between histones and allow the association of transcription factors or polymerase on open DNA. For example, H3K27 trimethylation by the polycomb complex PRC2 causes chromosomal compaction and gene silencing. These histone modifications may be created by the cell, or inherited in an epigenetic fashion from a parent.
Transcription factors and enhancers
Transcription factors are proteins that bind to specific DNA sequences in order to regulate the expression of a given gene. The power of transcription factors resides in their ability to activate and/or repress wide repertoires of downstream target genes. The fact that these transcription factors work in a combinatorial fashion means that only a small subset of an organism’s genome encodes transcription factors.
Transcription factors function through a wide variety of mechanisms. Often they are at the end of a signal transduction pathway that functions to change something about the factor, like its subcellular localization or its activity. 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.
Transcription factors can be divided in two main categories: activators and repressors. While activators can interact directly or indirectly with the core machinery of transcription through enhancer binding, repressors predominantly recruit co-repressor complexes leading to transcriptional repression by chromatin condensation of enhancer regions.
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.
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. 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.
The configuration of the genome is essential for enhancer-promoter proximity. 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.
In vertebrates, the majority of gene promoters contain a CpG island with numerous CpG sites. When many of a gene’s promoter CpG sites are methylated the gene becomes silenced.
Colorectal cancers typically have 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations.
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. Transcriptional repression in cancer can also occur by other epigenetic mechanisms, such as altered expression of microRNAs.
In breast cancer, transcriptional repression of BRCA1 may occur more frequently by over-expressed microRNA-182 than by hypermethylation of the BRCA1 promoter.
History & Conclusion
A molecule that allows the genetic material to be realized as a protein was first hypothesized by François Jacob and Jacques Monod. These French scientists eventually got a Nobel for their work on molecular biology. Severo Ochoa won a Nobel Prize in Physiology or Medicine in 1959 for developing a process for synthesizing RNA in vitro with polynucleotide phosphorylase, which was useful for cracking the genetic code. RNA synthesis by RNA polymerase was established in vitro by several laboratories by 1965; however, the RNA synthesized by these enzymes had properties that suggested the existence of an additional factor needed to terminate transcription correctlly. In 1972, Walter Fiers became the first person to actually prove the existence of the terminating enzyme. Roger D. Kornberg won the 2006 Nobel Prize in Chemistry “for his studies of the molecular basis of eukaryotic transcription”. (See section of Nobel Prizes).
Transcription regulation glossary
• transcriptional regulation – controlling the rate of gene transcription for example by helping or hindering RNA polymerase binding to DNA
|• transcription – the process of making RNA from a DNA template by RNA polymerase|
|• 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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