Genome-wide analysis of promoter contacts identifies novel regulators of late-stage adipogenesis

Abstract

SUMMARYAdipogenesis is a multi-step process, with epigenetic mechanisms and dynamic 3D chromatin folding thought to play important regulatory roles. However, the kinetics and functional roles of promoter contacts during late-stage adipogenesis are unknown. Here, using multi-omics approaches, we found evidence for promoter switching and widespread 3D rewiring of promoter contacts, as well as changes in the transcriptome and epigenome in late-stage adipogenesis. We identified several clusters of promoter contacts with unique temporal profiles suggesting crucial roles for distal enhancers. By integrating transcriptomics, promoter-capture Hi-C and a siRNA screen of druggable genes, we identified 19 novel regulators of late-stage adipogenesis, over half of which have peptidase or ubiquitin-protein ligase activities. Population-based genetic analyses showed that three of the 19 genes (LAP3,CELA1andGPR157) are involved in regulation of adiposity in humans. These findings shed new light on the epigenetic regulation of late-stage adipogenesis, advancing our understanding of the mechanisms that underpin the formation of functional adipocytes and identifying potential targets for preventing/treating obesity and related disorders.