JARID1a in circadian control of hepatic energy metabolism

项目总结 在哺乳动物中，昼夜节律振荡器已经成为新陈代谢和能量的关键协调器。 动态平衡。重要的是，由环境因素引起的昼夜节律失调在现代 生活方式(时差、轮班工作、人为延长的光周期、西方饮食)与体重有关 增重、代谢综合征和糖尿病。生物钟和能量之间的重要联系 新陈代谢发生在表观遗传控制水平上。然而，时钟是如何影响基因调控的 通过表观遗传机制实现的能量动态平衡还没有完全被理解。特别是，它的影响 时序紊乱和西式饮食对表观遗传调节功能和机制的影响 它们反过来又对代谢性疾病的发展起到了什么作用，目前尚不清楚。我们之前 将JmjC类赖氨酸去甲基酶JARID1a描述为昼夜节律振荡器的非冗余组件。 最近，我们观察到JARID1a的肝脏特异性消融会导致葡萄糖代谢的中断。 这一建议使用了新的组织特异性遗传小鼠模型、明暗时间表和饮食 操纵、分子生物学技术和基因组学方法将JARID1a描述为一个新的 时间破坏性环境变量和代谢功能障碍之间的表观遗传学联系。基于 初步数据，这一提议检验了JARID1a是表观遗传联系的中心假设 昼夜节律与基因组对糖代谢的反向调控 CREB和ChREBP因子，它们的功能失调会扰乱血糖稳态。在我们的第一个目标中，我们 询问高脂肪饮食、脂肪酸、禁食、急性进食、打乱时间的日程表的影响 JARID1a功能上的代谢信号通路。在我们的第二个目标中，我们研究分子机制。 JARID1a通过对抗两个重要的葡萄糖调节器来调节能量代谢 稳态：转录因子CREB和ChREBP。

PROJECT SUMMARY In mammals, the circadian oscillator has emerged as a critical orchestrator of metabolism and energy homeostasis. Importantly, circadian dysfunction due to environmental factors commonly found in modern lifestyles (jet lag, rotating shift work, artificially-extended photoperiod, western diets) has been linked to weight gain, metabolic syndrome, and diabetes. An important connection between the circadian clock and energy metabolism occurs at the level of epigenetic control. However, how the clock bears upon genomic regulation of energy homeostasis through epigenetic mechanisms is not fully understood. In particular, the effects that chronodisruption and western-style diets have on the function of epigenetic regulators and the mechanisms by which they, in turn, contribute to the development of metabolic disease remains unknown. We previously described the JmjC-class lysine demethylase JARID1a as a non-redundant component of the circadian oscillator. Recently, we have observed that liver-specific ablation of JARID1a results in disruptions to glucose metabolism. This proposal uses a combination of novel tissue-specific genetic murine models, light-dark schedule and dietary manipulations, molecular biology techniques, and genomic approaches to characterize JARID1a as a novel epigenetic link between chronodisruptive environmental variables and metabolic dysfunction. Based on preliminary data, this proposal tests the central hypothesis that JARID1a is an epigenetic link between the circadian clock and genomic regulation of glucose metabolism through opposing modulation of the transcription factors CREB and ChREBP, and whose dysfunction disrupts glucose homeostasis. In our first aim, we interrogate the impact of a high-fat diet, fatty acids, fasting, acute feeding, chronodisrupted light schedules, and metabolic signaling pathways on JARID1a function. In our second aim, we investigate the molecular mechanisms by which JARID1a regulates energy metabolism through opposing control of two important regulators of glucose homeostasis: the transcription factors CREB and ChREBP.