Epigenetic Approaches to Adipose Biology

Abstract

Adipocytes play a major role in many metabolic diseases. To understand how adipocyte function is regulated in health and disease, we have focused on identifying and characterizing the transcriptional pathways that regulate differentiation, insulin sensitivity, lipogenesis, and lipolysis. Traditional strategies to accomplish these goals rely upon the discovery of candidate factors that may come to researchers’ attention because of homology, expression, or an unexpected phenotype in a knockout animal, for example. In contrast, we have developed strategies to map epigenetic alterations in adipocytes, reasoning that this information can be used to identify novel pathways that would have been difficult to predict otherwise. In initial proof-of-principle studies, we employed a high-throughput DNase hypersensitivity analysis in developing adipocytes. These experiments led us to identify interferon regulatory factors (IRFs) and the nuclear receptor, Nr2f2, as key players in adipocyte differentiation. Despite the success of this approach, there were temporal, spatial, and functional biases that prevented a truly comprehensive analysis. We have therefore performed a genome-wide analysis using ChIP-Seq-based mapping of modified histones in two species (mouse and human) and at four distinct developmental time points, providing an unprecedented look at chromatin state changes over the course of cellular differentiation. These studies will allow us to draw inferences about the transcriptional control of adipocyte function and open the door for downstream studies that directly address metabolic disease.