PROJECT SUMMARY (See instructions): 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. During the mentored phase of this award, I focused on the following Aims: (1) Studying how acyl reader complexes regulate gene expression under particular cell contexts, (2) Determining how histone acylations regulate intestinal epithelial cell fate. In this next independent phase of this award, I will continue studying mechanisms of how different acyl marks are regulated and focus on Aim 3: Investigating the regulation of histone acylations through cellular metabolism. This proposed work will utilize skills built during my postdoctoral training and the mentored phase of this award to foster my success as an independent scientist. Together, completion of this research proposal will elucidate the connection between metabolism and chromatin and further advance our understanding of the physiological roles of novel histone acyl marks.

RELEVANCE (See instructions): Gene expression is a tightly regulated and fundamental cellular process that is vital for organismal physiology and is often altered in disease. These studies aim to understand molecular mechanisms that govern gene expression through the chromatin landscape in response to changing environmental stimuli, including alterations in the microbiota and cellular metabolism, and resulting impacts on cell biology.