Integration of metabolism and chromatin in regulating gene expression in vivo

项目摘要 了解细胞如何响应不断变化的环境线索的分子机制， 各种信号，特别是在复杂组织或有机体的情况下，是一个主要的挑战。在 在哺乳动物的肠道中，来自饮食和肠道微生物群的输入可以以代谢物的形式出现， 作用于邻近的肠上皮细胞并影响生理学。其中一类代谢物是短链的 脂肪酸（SCFAs），由微生物通过分解膳食纤维产生。最近，SCFA 已被检测为组蛋白上的化学修饰，称为组蛋白酰化。虽然某些 组蛋白酰化作用已被报道为正调控转录，包括已被充分研究的组蛋白 乙酰化，其他酰基标记的机械功能作用，特别是它们的生理作用，在很大程度上是 未知此外，染色质景观的改变可以对基因调控产生影响， 表达和下游细胞功能。因此，我的总体目标是获得机械的理解， 组蛋白酰化是如何调节和支配体内细胞功能的。我的核心假设是， 组蛋白酰化通过在特定组织中发挥不同的作用而在基因调控中具有不同的功能 和基因组，外源性信号调节组蛋白酰化的平衡， 表型我将使用小鼠肠道作为模型系统，这将可能阐明生理学 本论文的主要目的是：（1）研究组蛋白酰基标记物的功能及其调控机制 酰基阅读器复合物如何在特定的细胞环境下调节基因表达，（2）我将确定如何 组蛋白酰化调节肠上皮细胞的命运，（3）我将研究组蛋白酰化对肠上皮细胞命运的调节。 通过细胞代谢进行酰化。这项拟议中的工作将重要地建立了我的博士后研究 并将为我提供成为独立调查员的关键培训。在指导期间， 在这个奖项的第一阶段，我将获得动物工作，染色质生物学和新陈代谢方面的基本培训。这种支持， 沿着洛克菲勒大学杰出的环境和阿利斯博士的指导，将使我 为这个奖项的独立部分的成功。重要的是，我将继续促进合作， 接受我的咨询委员会的额外指导，他们将提供肠道方面的关键专业知识， 微生物群和新陈代谢，促进我向独立的过渡。这些培训和支持将共同 促进我的科学事业，完成这项研究计划将促进我们对 新的组蛋白酰基标记的生理作用。

Project Summary Understanding the molecular mechanisms of how cells respond to changing environmental cues and integrate various signals, especially in the context of an intricate tissue or organism, is a major challenge. In the mammalian intestine, inputs from diet and the commensal microbiota can occur in the form of metabolites that act on neighboring intestinal epithelial cells and impact physiology. One such class of metabolites are short chain fatty acids (SCFAs), which are generated by microbes through the breakdown of dietary fiber. Recently, SCFAs have been detected as chemical modifications on histone proteins, called histone acylations. While certain histone acylations have been reported to positively regulate transcription, including the well-studied histone acetylation, the mechanistic functional role of other acyl marks and especially their physiological roles, are largely unknown. In addition, alterations in the chromatin landscape can have consequences on the regulation of gene expression and downstream cellular functions. Thus, my overall goal is to gain mechanistic understanding of how histone acylations are regulated and govern cell function in vivo. My central hypothesis is that different histone acylations have distinct functions in gene regulation through playing different roles in particular tissues and gene sets, and that exogenous cues regulate the balance of histone acylations that can drive cellular phenotypes. I will use the murine intestinal tract as a model system, which will likely elucidate physiological functions and delineate regulatory mechanisms of histone acyl marks through the following Aims: (1) I will study how acyl reader complexes regulate gene expression under particular cell contexts, (2) I will determine how histone acylations regulate intestinal epithelial cell fate, and (3) I will investigate the regulation of histone acylations through cellular metabolism. This proposed work will importantly build off of my postdoctoral studies and will provide me with critical training towards becoming an independent investigator. During the mentored phase of this award, I will gain essential training in animal work, chromatin biology, and metabolism. This support, along with the outstanding environment at Rockefeller University and mentorship from Dr. Allis, will set me up for success for the independent portion of this award. Importantly, I will continue to foster collaborations and receive additional mentoring from my Advisory Committee, who will provide crucial expertise in the intestine, microbiota, and metabolism, and facilitate my transition to independence. Together, this training and support will promote my scientific career and completion of this research proposal will advance our understanding of the physiological roles of novel histone acyl marks.