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.