Determining how distinct vertebrate promoter classes coordinate cis-regulatory input. (360G-Wellcome-110286_Z_15_Z)

Highly coordinated gene regulation is essential for multicellular development and when perturbed can lead to disease. Normal transcriptional regulation relies on communication between gene promoters and distal regulatory elements (DREs)[9,10], a process that appears to involve extensive interactions between these sites[11-13]. However, the mechanisms driving these interactions remain poorly understood, limiting our capacity to fully understand gene regulation. In order to bridge this major conce ptual gap, I will use cutting-edge genomic and evolutionary approaches to determine how promoters engage with their respective DREs. This will be achieved by focussing on the two major vertebrate promoter types, CpG-rich and CpG-poor, and detailing promoter/DRE interactions in mouse embryonic stem cells. I will then genetically perturb CpG-rich promoter chromatin to determine how chromatin architecture contributes to the establishment of these interactions. Building on this work, I will identify promoter/DRE contacts in related yet divergent vertebrate species to understand how interactions form and are affected by genomic arrangements during evolution. This ground-breaking study will provide novel insight into how promoter type, chromatin architecture and genomic organisation contribute to promoter/DRE interactions, significantly advancing our understanding of gene regulation.