Mechanisms of gene expression

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

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Abstract

Transcriptional regulation is the means whereby cells orchestrate expression of individual genes or group of genes. Recent studies with single cells have shown that, for the most part, transcription is not a continuous activity but it occurs in bursts. The amount of RNA produced for each gene is directly proportional to the amplitude and frequency of such bursts. How these two parameters are controlled is not totally clear, but it appears that DNA sequence information at promoters determine the amplitude, while burst frequencies rely on sequence information at enhancers. Promoters and enhancers are also known as gene regulatory elements. their primary role is to recruit enzymes (polymerases) and other key proteins (transcription factors, activators and inhibitors) that open up the DNA helix and read the genetic information. Another important feature of promoters and enhancers is that to function properly they must either be in close proximity or in contact with each other. This fiscal year, our laboratory has explored how the cell facilitate contacts between regulatory DNA to drive transcription. Our key publication in this area: 1- El Khattabi et al. Cell, August 2019. In this manuscript we have shown that a large complex known as Mediator recruits RNA polymerases to gene promoters in mammalian cells. Once at promoters, Mediator undergoes a drastic structural change (probably by associating with transcription factors) which in yeast drives phosphorylation of polymerases, an activity essential for transcription. Finally, contrary to current models, we have found that Mediator is not required for the tethering of promoters and enhancers. The new findings therefore shed light on how transcription is regulated in higher organisms.