Transcriptional and Epigenomic Analysis of Metabolism

A core mission of the lab is to develop a regulatory map of gene expression in metabolically relevant cell types, particularly adipocytes. We employ many different approaches to identify novel transcriptional pathways in normal and dysfunctional adipose tissue, most of which rely upon epigenomic strategies. Mapping active cis-regulatory elements in different states (e.g., pre-adipocytes vs. adipocytes, or brown vs. white adipocytes) allows us computationally to infer cognate binding proteins, which we then validate with wet lab techniques in vitro and in vivo. We have used a variety of chromatin state mapping methods (e.g., ATAC-seq, modified histone ChIP-seq, and DNase hypersensitivity) integrated with transcriptional profiling to address the transcriptional networks that affect adipogenesis, thermogenesis, and insulin resistance in adipocytes (PMIDs: 20887899, 21356515). Although we performed much of our earlier work in cell culture, we have since moved into more physiological models in vivo. Since many tissues are complex and highly heterogeneous, we developed a new mouse model that allows us to “tag” the nuclei and translating ribosomes of specific cell types in order to obtain cell type-specific transcriptional and epigenomic profiles (PMID: 28122230). We have used this model to determine how chromatin state changes in brown, beige, and white adipocytes during a temperature shift (PMID: 29657031). We are also pursuing similar strategies in other cells of metabolic importance, such as hepatocytes and AgRP and POMC neurons from the hypothalamus.