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

Adipogenesis 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, CELA1 and GPR157) 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. ### Competing Interest Statement S.S. is a co-founder and shareholder of Enhanc3D Genomics. J.R.B.P. is an employee and shareholder of Adrestia Therapeutics Ltd. and receives research funding from GSK.