The precise regulation of gene expression is a finely tuned process that is essential for cellular homeostasis, and the misregulation of transcription occurs in disorders and diseases that impact human health, including cancer. The chromatin landscape integrates diverse cellular signals to regulate genome structure and subsequent biological functions, partly through posttranslational modifications (PTMs) on histone proteins. Many donor molecules for histone PTMs are metabolites (e.g., acetyl-CoA is utilized for acetylation), which directly links cellular metabolism to the chromatin landscape. Yet the direct mechanisms and functional significance of the metabolic regulation of chromatin is largely lacking, especially in in vivo settings. We focus on using the mammalian intestine as a model to study the impacts of environmental cues on different aspects of cell biology via metabolism, since the intestine a powerful tissue system in which epithelial cells are subject to diverse environmental stimuli. Here, we study molecular mechanisms that control gene regulation and subsequent cell function in the context of chromatin to answer key questions about gene regulation in health and disease.
MECHANISMS OF METABOLITE SIGNALING TO CHROMATIN
The chromatin landscape is linked to metabolism, since many donor molecules for histone PTMs are small metabolites. Alterations in the microbiota and diet regulates both the intestinal chromatin landscape and gene expression programs. Now, we aim to understand mechanisms of how these chromatin changes in these physiological contexts relate to specific responses in gene regulation. We aim to trace metabolite signaling to chromatin, investigate how chromatin readers and other proteins interact with histone PTMs, and study the functional role of novel metabolite-derived histone PTMs, including histone butyrylation.
THE ROLE OF CHROMATIN IN INTESTINAL CELL FATE
The intestinal epithelium is estimated to be replaced every 3-5 days, providing a unique environment in which epithelial cells must undergo continuous proliferation, migration, and differentiation to specialized cell types. Furthermore, different types of intestinal epithelial cells have distinct metabolic profiles and needs depending on their location in the epithelium and metabolic zones (i.e., crypt vs villi), growth needs, and specialized cell functions. However, the question of how the chromatin landscape changes across cell fates and the functional significance of different chromatin states in intestinal cell identity is largely unknown. We aim to define how chromatin regulates intestinal cell fate, and how specific intestinal cell populations or niches respond to environmental signals.
METABOLISM & CHROMATIN IN DISEASE
One hallmark of cancers is altered metabolism, which can be exploited for diagnostic and therapeutic uses. Changes in cellular energy needs with transformation and signaling within the local microenvironment can impact cellular metabolism, which in turn can regulate chromatin modifications, partly through the availability of metabolites and the altered activity of chromatin modifying enzymes. In addition, environmental changes (i.e., diet, microbiota) can also regulate tumorigenesis. Now, we are studying how alterations in metabolism change how cells respond to environmental cues and impact tumorigenesis, as well as how cancer-associated mutations in chromatin modifying enzymes alter the intersection between metabolism and chromatin.