Nuclear Repressors in Genomic Control of Healthful Obesity

项目总结 非酒精性脂肪性肝病(NAFLD)困扰着近四分之一的美国人，预计将成为 未来十年终末期肝病的主要原因。它是由营养过剩驱动的，不成比例地发生 在男性中，并与肝脏脂肪和类固醇代谢紊乱有关。这些分子决定因素 控制非酒精性脂肪肝及其性别偏见的研究还不完全清楚。使用条件基因工程，我们有 发现转录因子B细胞淋巴瘤6(BCL6)在指导性二型性方面发挥着深远的作用 肝细胞中的转录。在这里，我们建议全面剖析转录调控 BCL6的性别特异性编程机制及肝细胞BCL6的功能意义 论脂肪肝与全身新陈代谢。在目标1中，我们将测试BCL6对染色质环路的影响 和组蛋白修饰，其性别特异性的重新聚集到染色质的方式，以及与雌激素的共同调节 受体阿尔法。在目标2中，我们定义了bcl6在NAFLD的性别二型性中的功能作用，它的信号转导 通过胆汁酸途径，以及它对体内功能丧失和功能获得的研究对纤维化的影响。一起， 这些研究将揭示对性二态转录和调控的新的分子见解 NAFLD。

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.