# Chromatin regulation of epithelial stem cell function

> **NIH NIH R35** · EMORY UNIVERSITY · 2021 · $387,021

## Abstract

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.

## Key facts

- **NIH application ID:** 10272880
- **Project number:** 1R35GM142503-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Adam David Gracz
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $387,021
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10272880

## Citation

> US National Institutes of Health, RePORTER application 10272880, Chromatin regulation of epithelial stem cell function (1R35GM142503-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10272880. Licensed CC0.

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