Transcription by Prof Sridhar Hannenhalli

To express or not

Here now a bit or a lot

That is the question.

 

Every cell in an organism contains an identical copy of the genome, except for rare somatic mutations, that encodes its entire gene complement. Yet, each of the hundreds of individual cell types in an organism utilizes a well-defined subset of the genes – imagine your neurons expressing genes that are normally expressed in skin cells. Thus the cell, starting from the single-celled embryo, must have a mechanism to control when, and how much of, each gene is expressed. This control is exercised, in large part, at the level of transcription – the process of reading the DNA encoding a gene on the genome and copying it into a messenger RNA (mRNA), which is eventually translated into the final protein product (or otherwise processed into a final RNA product).

Besides controlling normal development and defining the identity of individual cells, the response to a change in environment is also managed at the level of transcription.  This was first demonstrated by Jacques Monod and Francois Jacob in their seminal 1961 paper, showing that a group of E. coli genes that encode for proteins required to break down lactose is transcriptionally switched on or off depending on whether the growth medium is rich in lactose or glucose. They went on to win the 1965 Nobel Prize in Physiology or Medicine for their discovery.

Transcriptional control plays a critical role not only in development and environmental response, but also at a longer time scale in mediating evolutionary divergence across species. In their classic 1975 paper, Mary-Claire King and Alan C Wilson, observing very high levels of similarity between several proteins of chimpanzees and humans, concluded that the vast phenotypic differences between the two species could not be explained by such small degree of molecular divergence and are likely to be driven by the changes in the mechanisms controlling the gene transcription.

The role of transcriptional control in dictating natural diversity at multiple natural scales from cells within an organism, individuals within a species, and across species is now well established. This extends even to phenotypic changes associated with all complex diseases, and is underscored by the observation that the vast majority of genotypic signals associated with human diseases reside in non-protein-coding regions of the genome, thus focusing the research efforts in interpreting these signals in the context of transcriptional control.

Original research:

Jacob, F. & Monod, J. (1961) Genetic regulatory mechanisms in the synthesis of proteins. J Mol Biol 3, 318–356.  http://biotheory.phys.cwru.edu/phys320/JacobMonod1961.pdf

King, M. C. & Wilson, A. C. (1975) Evolution at two levels in humans and chimpanzees. Science (80) 188, 107–116. https://doi.org/10.1126/science.1090005

Hindorff, L. A. et al. (2009)Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. PNAS 106, 9362–9367.  https://doi.org/10.1073/pnas.0903103106

Sridhar Hannenhalli is professor of Cell Biology and Molecular Genetics at the UMD, interested in transcriptional regulation and evolution. He is currently visiting IISc, Bangalore, as a Fulbright scholar. You can follow him on twitter @hannenhalli.

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