Chromatin regulation of epithelial stem cell function

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ABSTRACT Stemness is a functional cellular attribute defined by properties of multipotency (the ability to produce all differentiated cell types in a tissue) and self-renewal (the ability to produce new stem cells). In adult epithelial tissues, stemness can exist in: (1) dedicated stem cells occupying a defined niche, and (2) differentiated cells that exhibit plasticity to drive regeneration following injury. Stem cells must balance self-renewal with differentiation, and differentiated cells must balance lineage specific identity with plasticity to participate in regenerative responses. My lab is interested in understanding how chromatin modifications and their associated enzymes interact with site-specific transcription factors (TFs) to establish cell identities while simultaneously facilitating alternative cell fates. We focus on intestinal stem cells (ISCs), which drive the renewal of the intestinal epithelium approximately once a week throughout adult life, as a model system. Over the next five years, my research program will explore how TFs and chromatin modifying enzymes contribute to an exit from the stem cell state as ISC differentiate. Current models propose that rapid differentiation and plasticity in the intestinal epithelium is regulated by chromatin landscapes that are highly similar across all intestinal epithelial cell types, regardless of differentiation stage. Recent studies in my lab have challenged this model using a Sox9EGFP mouse model that allows us to isolate ISCs, progenitors, and differentiated cells with a single reporter transgene. We quantified changes in chromatin accessibility and 5-hydroxymethylcytosine and identified significant chromatin dynamics at genomic loci consistent with enhancers. Our analyses identified novel candidate TF-chromatin interactions and raise exciting questions about the importance of chromatin regulation in adult epithelial stem cells. Our future research will build on this progress to understand: (1) how stem cell- associated chromatin is decommissioned by TFs in differentiation, (2) how lineage-specific regulatory programs are “primed” in ISCs, and (3) how chromatin modifying enzymes bridge regulation of self-renewal and differentiation. The approach proposed here will establish a long-term research program, with broad potential to expand into studies of plasticity/de-differentiation, chromatin regulation of epithelial responses to environmental challenges, and development. Our goal is to pursue a basic mechanistic understanding of chromatin regulation in stemness that will have foundational relevance to human health and disease, including epithelial responses to inflammation, infection, injury, aging, and tumorigenesis.