University of Cambridge > > Cancer Research UK Cambridge Institute (CRUK CI) Seminars in Cancer > Transcriptional Lego: Predictable control of gene expression by manipulating promoter building blocks

Transcriptional Lego: Predictable control of gene expression by manipulating promoter building blocks

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The ability to control the timing and levels at which genes are expressed is key to most biological processes. Although we know the sequence preferences of key players in this process, we are still far from understanding how these elements combine within regulatory sequences to encode the transcriptional outcome. Based on our theoretical analyses, we devised hypotheses regarding the effect that different nucleosome disfavoring sequences that vary in length, composition, and distance from transcription factor binding sites, will have on the transcriptional outcome. To systematically test these hypotheses, we designed and synthesized ~80 promoter sequences, and fused each promoter to a fluorescent reporter, resulting in the largest library of designed promoter variants to date. Our results show that by manipulating either or both transcription factor binding sites and nucleosome disfavoring sequences in the vicinity of the site, we can tune expression levels in a predictable manner. Importantly, sequence changes that only alter nucleosome disfavoring sequences result in effects on expression comparable in magnitude to those that result from changes to transcription factor binding sites. In fact, compared to binding site changes, alterations of nucleosome disfavoring sequences likely yield more gradual changes in expression levels, and thus offer means to fine-tune gene expression with high resolution. These results have intriguing implications for evolution of gene expression, suggesting that sequence changes that alter the DNA -encoded nucleosome organization may provide an efficient genetic mechanism by which genomes may evolve and fine-tune gene expression. Overall, our results bring us a step closer towards understanding the role of various promoter elements and their combined effects on transcription, and suggest that directed design of promoter sequences that yield pre-specified expression patterns may be within reach.

This talk is part of the Cancer Research UK Cambridge Institute (CRUK CI) Seminars in Cancer series.

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