# Investigating a master regulator of large intestine stem cells

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $507,280

## Abstract

PROJECT SUMMARY
The colon is a major segment of the intestine and differs significantly from the small intestine in
morphology, cell types, physiological function and disease susceptibility. Devastating and prevalent
diseases, including colorectal cancers and ulcerative colitis, arise from colon but not small intestine.
Colon absorbs water but cannot uptake most nutrients like the small intestine and consequently a
significant loss of the small intestine will lead to digestive failure that the colon cannot compensate.
Despite significant progress, aspects of the colon biology remain poorly understood. Molecular
determinants that distinguish the colon from the small intestine and govern colon-specific cell lineage
differentiation and homeostasis remain largely uncharacterized, hindering a deeper understanding of
regionalized intestinal diseases. In preliminary studies, we identified SATB2, a chromatin factor with
restricted expression in the colonic epithelium, as a crucial molecular regulator of colon identity and
differentiation. SATB2 deletion from adult intestine led to a homeotic-like transformation of colonic
epithelium into one that resembles small intestine ileum in cellular composition and gene expression,
and the mutant colon can absorb nutrients, a function unique to the small intestine. These data
suggest that SATB2 is a potential “master regulator” of colonic epithelium. The identification of SATB2
offers a unique opportunity to study colonic ontogeny and fate determination, and assess its
therapeutic implications. In this project, Aim 1 will evaluate the hypothesis that colonic stem cells
harbor primed ileal enhancers and thus harbor a chromatin-level permissiveness for ileal
transcriptional activation and cell fate plasticity. Aim 2 studies will evaluate the hypothesis that SATB2
recruits two chromatin remodeling factors, MTA2 and SMARCD2, to separate pools of colonic and
ileal enhancers to modify local chromatin, allowing differential access of intestinal transcription factors
and effecting transcriptional regulation. In Aim 3, using mouse models of Short bowel syndrome
(SBS), we will evaluate whether promoting colonic nutrient absorption can combat digestive failure
and the associated pathophysiology in SBS. These studies together will elucidate the cellular and
molecular mechanisms by which SATB2 preserves colonic identity and effects a colonic to ileal
conversion, which may be exploited as a novel therapeutic approach to treat SBS.

## Key facts

- **NIH application ID:** 10458677
- **Project number:** 5R01DK125817-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Qiao Joe Zhou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $507,280
- **Award type:** 5
- **Project period:** 2021-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10458677

## Citation

> US National Institutes of Health, RePORTER application 10458677, Investigating a master regulator of large intestine stem cells (5R01DK125817-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10458677. Licensed CC0.

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