Integration of metabolism and chromatin in regulating gene expression in vivo

项目摘要 了解细胞如何对变化的环境线索作出反应和整合的分子机制 各种信号，特别是在复杂组织或有机体的背景下，是一个重大挑战。在 哺乳动物肠道、来自饮食的输入和共生微生物区系可以以代谢物的形式出现， 作用于邻近的肠道上皮细胞并影响生理。一类这样的代谢物是短链 脂肪酸(SCFA)，由微生物通过分解膳食纤维而产生。最近，SCFA 已经被检测到是组蛋白的化学修饰，称为组蛋白酰化。虽然可以肯定 组蛋白酰化已被报道为正向调节转录，包括研究得很好的组蛋白。 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 未知。此外，染色质景观的改变会对基因的调控产生影响。 表达和下游细胞功能。因此，我的总体目标是机械地理解 组蛋白酰化如何在体内调节和支配细胞功能。我的中心假设是不同的 组蛋白酰化通过在特定组织中扮演不同的角色而在基因调控中发挥不同的功能 和基因组，以及外源信号调节组蛋白酰化的平衡，从而驱动细胞 表型。我将使用小鼠肠道作为一个模型系统，这可能会阐明生理学 通过以下目的描述组蛋白酰基标记的功能和调控机制：(1)我将研究 酰基阅读器复合体如何在特定细胞环境下调节基因表达，(2)我将确定如何 组蛋白酰化作用调节肠上皮细胞命运，以及(3)我将研究组蛋白的调节。 通过细胞新陈代谢进行酰化反应。这项拟议的工作将重要地建立在我博士后研究的基础上 并将为我提供成为一名独立调查员的关键培训。在接受指导的过程中 在这个奖项的阶段，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， 再加上洛克菲勒大学的出色环境和艾利斯博士的指导，将会让我 为该奖项的独立部分取得成功。重要的是，我将继续促进合作和 接受我的咨询委员会的额外指导，他们将提供关键的肠道专业知识， 微生物区系，和新陈代谢，并促进我向独立的过渡。联合起来，这种培训和支持将 促进我的科学事业，完成这项研究方案将增进我们对 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.