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.