Reconstructing the functional gene regulatory circuitry of adipocytes
In highly collaborative work with Evan Rosen, we aim to systematically identify the functional components of the adipocyte epigenome, providing insight into the regulatory circuits that transform signals into cellular responses such as differentiation and insulin resistance. We utilize genome scale techniques such as histone modification ChIP-seq, ATAC-seq, RNA-seq and Hi-C to profile in an unbiased way the dynamic cis-regulatory elements that control gene expression. Using mouse and human samples across a spectrum of genetic, environmental and disease states (particularly obesity and insulin resistance), we utilize computational approaches to reconstruct the molecular circuits underlying variation in transcription. We are now testing and validating these models by systematically perturbing circuit elements and monitoring effects on circuit output using genome wide perturbation approaches such as CRISPRa and CRISPR KO in in vitro models of adipogenesis and adipocyte function. A major focus of this work is to better understand the effects of genetic variation on molecular phenotypes in adipocytes and their effects on human disease. Integrating our functional genomic data with genetic association we aim to identify likely causal variants and to predict the effects of genetic perturbations.