Bioinformatics Molecular Biology

Transcriptional Regulation

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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. The regulation of transcription is a vital process in all living organisms. 

Transcription regulation is carefully coordinated with DNA replication and chromosome segregation. In E. coli and in other bacteria and bacteriophages, heavily transcribed genes are oriented such that replication and transcription occur in the same direction. Despite this arrangement, because DNA replication occurs 10–20 times faster than transcription, RNA polymerase and DNA polymerases do collide. The outcome of such an encounter is hard to predict. 

Transcriptional regulation is a critical biological process that allows the cell or an organism to respond to a variety of intra- and extra-cellular signals, to define cell identity during development, to maintain it throughout its lifetime, and to coordinate cellular activity. This highly dynamic mechanism includes a series of biophysical events orchestrated by a huge number of molecules establishing larger networks and occurring through multiple temporal and functional steps that range from specific DNA-protein interactions to the recruitment and assembly of nucleoprotein complexes. Essentially, the key transcription levels include the recruitment and assembly of the entire transcription machinery, the initiation step, pause release and elongation phases, as well as termination of transcription. Additionally, these steps are interconnected with governing chromatin accessibility (such as the unwrapping process, which is controlled by histone modification and chromatin remodeling proteins), and other epigenetic mechanisms (such as enhancer-promoter looping, which is necessary for a successful gene transcription). Finally, various RNA maturation events, such as the splicing that occurs with transcription, constitute an additional level of complexity. Numerous molecules and molecular factors, including transcription factors, cofactors (both coactivators and corepressors), and chromatin regulators, are known to participate in this process.

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. The 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.

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 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 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
  • 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.
  • A number of factors which have been found to control how and when termination occurs, which will dictate the fate of the RNA transcript.

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