Nuclear Repressors in Genomic Control of Healthful Obesity

点击翻译按钮获取中文摘要

PROJECT SUMMARY Non-alcoholic fatty liver disease (NAFLD) afflicts nearly a quarter of Americans and is projected to become the leading cause of end-stage liver disease in the next decade. It is driven by overnutrition, disproportionately occurs in men, and is linked to derangements in liver lipid and sterol metabolism. The molecular determinants that control NAFLD and its sex-bias are incompletely understood. Using conditional genetic engineering, we have identified a profound role for the transcription factor B cell lymphoma 6 (BCL6) to direct sexually dimorphic transcription in hepatocytes. Herein, we propose to comprehensively dissect the transcriptional regulatory mechanisms of BCL6 underlying its sex-specific programming and the functional implications of hepatocyte Bcl6 on fatty liver disease and whole body metabolism. In Aim 1, we will test the impact of BCL6 on chromatin looping and histone modification, its sex-specific modes of recruitment to chromatin, and coregulation with estrogen receptor alpha. In Aim 2, we define the functional role of Bcl6 in the sexual dimorphism of NAFLD, its signaling through bile acid pathways, and its impact on fibrosis using loss- and gain-of-function studies in vivo. Together, these studies will reveal new molecular insights into the regulation of sexually dimorphic transcription and NAFLD.