Nuclear Repressors in Genomic Control of Healthful Obesity

项目摘要 非酒精性脂肪肝（NAFLD）困扰着近四分之一的美国人，预计将成为美国最严重的脂肪肝。 在未来十年中，终末期肝病的主要原因。它是由营养过剩驱动的， 在男性中，与肝脏脂质和固醇代谢紊乱有关。分子决定因素， 控制NAFLD和它的性别偏见是不完全理解。利用条件遗传工程，我们有 确定了转录因子B细胞淋巴瘤6（BCL 6）在指导性二态性 在肝细胞中的转录。在此，我们建议全面剖析转录调控基因， BCL 6的性别特异性编程机制和肝细胞Bcl 6的功能意义 对脂肪肝和全身代谢的影响。在目标1中，我们将测试BCL 6对染色质循环的影响 和组蛋白修饰，其性别特异性模式的招募染色质，并与雌激素的协同调节 α受体在目标2中，我们定义了Bcl 6在NAFLD的性二型性中的功能作用，其信号传导 通过胆汁酸途径，以及使用体内功能丧失和获得研究其对纤维化的影响。在一起， 这些研究将揭示性二态转录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.