Regulation of brown fat metabolism by histone demethylation

描述(由申请者提供)：我们的长期目标是了解能量平衡的转录基础，以及它的变化如何导致肥胖和代谢性疾病。棕色脂肪是一种专门消耗能量的组织。它存在于成年人身上，其活动与人类肥胖呈负相关。因此，棕色脂肪可能是治疗肥胖和代谢性疾病的有吸引力的靶向组织。我们感兴趣的是组蛋白甲基化和去甲基化的动力学如何调节棕色脂肪的发育和功能。我们发现，棕色脂肪基因的一个子集的启动子在前脂肪细胞中组蛋白H3的特定赖氨酸残基上发生甲基化，并在分化过程中去甲基化。我们进一步鉴定了在分化过程中负责去甲基化的去甲基酶。我们认为这种由去甲基酶催化的组蛋白甲基化在棕色脂肪的测定和代谢中起着关键作用。在第一个目标中，我们将详细研究这种去甲基酶，特别是它的去甲基化活性，在棕色脂肪基因表达和棕色脂肪细胞代谢中的作用，以及这种去甲基化酶是否是白色脂肪细胞向棕色脂肪细胞转化所必需的。在第二个目标中，我们将研究这种去甲基酶调节棕色脂肪的测定和功能的机制。我们将执行芯片序列来绘制这种去甲基酶及其底物的占位情况，这将为我们提供关于这种去甲基酶的全基因组、机制和功能的视图。在第三个目标中，我们将通过转基因小鼠和功能丧失研究来研究这种脱甲基酶在棕色脂肪代谢中的体内作用。

DESCRIPTION (provided by applicant): Our long-range goal is to understand the transcriptional basis of energy homeostasis and how its alteration contributes to obesity and metabolic diseases. Brown fat is a tissue that is specialized in energy expenditure. It is present is adult humans and its activity is inversely associated with human obesity. Thus, brown fat is potentially an attractive therapeutic target tissue for obesity and metabolic diseases. We are interested in how brown fat development and function is regulated by the dynamics of histone methylation and demethylation. We found that promoters of a subset of brown fat genes are methylated at a specific lysine residue of histone H3 in preadipocytes and are demethylated during differentiation. We further identified a demethylase that is responsible for the demethylation during differentiation. We propose that this demethylase-catalyzed removal of histone methylation plays a key role in brown fat determination and metabolism. In the first aim, we will investigate in detail the roles of this demethylase, in particular its demethylation activiy, in brown fat gene expression and brown fat cell metabolism, and whether this demethylase is required for conversion of white adipocytes to brown adipocytes. In the second aim, we will investigate the mechanism by which this demethylase regulates brown fat determination and function. We will perform ChIP-seq to map the occupancy of both this demethylase and its substrate, which will provide us a genome-wide, mechanistic and functional view of this demethylase. In the third aim, we will investigate the in vivo role of this demethylase in brown fa metabolism through both transgenic mice and loss-of-functional studies.