JARID1a in circadian control of hepatic energy metabolism

项目摘要 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者 体内平衡重要的是，由于现代人中常见的环境因素导致的昼夜节律功能障碍， 生活方式（时差，轮班工作，人为延长光照周期，西方饮食）与体重有关 体重增加、代谢综合征和糖尿病。生物钟和能量之间的重要联系 代谢发生在表观遗传控制水平。然而，时钟如何影响基因组调控， 通过表观遗传机制的能量稳态还没有被完全理解。特别是， 时间中断和西式饮食对表观遗传调节因子的作用和机制， 它们反过来又促进代谢疾病的发展仍然是未知的。我们之前 描述了JmjC类赖氨酸脱甲基酶JARID1a作为昼夜节律振荡器的非冗余组分。 最近，我们观察到肝脏特异性消融JARID1a导致葡萄糖代谢中断。 该建议使用了新的组织特异性遗传小鼠模型，光暗时间表和饮食的组合。 操作，分子生物学技术和基因组方法来表征JARID1a作为一种新的 时间破坏性环境变量和代谢功能障碍之间的表观遗传联系。基于 初步数据，这项提议测试了中心假设，即JARID1a是一个表观遗传联系， 生物钟和通过转录的反向调节对葡萄糖代谢的基因组调节 CREB和ChREBP因子，其功能障碍破坏葡萄糖稳态。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、时间打乱的光照时间表的影响， 代谢信号通路对JARID1a功能的影响在我们的第二个目标中，我们研究了分子机制， JARID 1a通过对抗两种重要的葡萄糖调节剂来调节能量代谢 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.