Towards a quantitative understanding of long-range transcriptional regulation

In mammals, control of gene expression relies on tens of thousands of enhancer sequences that are differentially active in every cell type. Enhancers engage with target promoters often from large genomic distances and govern their spatio-temporal and quantitative expression dynamics. Despite their central role in gene regulation in health and disease, however, the principles by which enhancers select and control their target genes remain largely unknown. What are the molecular mechanisms that transmit regulatory information from an enhancer to a promoter? How are they related to chromosome structure and physical interactions between enhancers and promoters? Are these mechanisms universal or rather depend on locus- and tissue-specific contexts? My group addresses these questions at the intersection of molecular biology and biophysics using a blend ofexperimental and theoretical approaches. In this talk I will present how using a combination of genomic engineering, physical modeling and live-cell imaging we recently discovered that a promoter’s transcription levels are a nonlinear function of its contact probabilities with an enhancer; how this could arise from dynamic and unstable physical contacts being translated into transcriptional events at the promoter; and how these results establish general quantitative principles for the role of chromosome structure in long-range transcriptional regulation.

References

Zuin, Roth et al 2021 https://www.biorxiv.org/content/10.1101/2021.04.22.440891v1

Mach, Kos, Zhan et al 2022 https://www.biorxiv.org/content/10.1101/2022.03.03.482826v1.full

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