Transcriptional and epigenomic analysis of insulin sensitivity in human adipocytes

Insulin resistance is a key feature of type 2 diabetes (T2D) and is also associated with a wide variety of other disease states. We isolated adipocytes from subjects with and without insulin resistance and subjected them to transcriptional and epigenomic profiling, allowing us to identify genes, cis-regulatory elements, and pathways that associate with insulin resistance in this critical cell type. We focused on several differentially enriched regions near the IRS1 gene that were close to, but distinct from, single-nucleotide polymorphisms associated with T2D and insulin resistance. CRISPR interference (CRISPRi)-mediated repression of these elements identified two major enhancer regions that regulate IRS1 expression in a cell-state-dependent manner. Finally, we identified specific transcription factors that act through these sites to enhance IRS1 gene expression. These studies help to define the molecular events that characterize, and potentially determine, human insulin sensitivity and resistance.