# Transcriptional control and enhancer recruitment in mouse and human intestinal secretory differentiation

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2024 · $357,716

## Abstract

PROJECT SUMMARY
 Intestinal secretory (Sec: goblet (Gob), enteroendocrine (EE), Paneth (Pan), and tuft) cells serve vital
digestive, metabolic, barrier, and other physiologic functions. Intestinal stem cells (ISCs) replenish both
absorptive and Sec epithelial cells, but the origins of Sec diversity and census are largely unknown. Because
it has been difficult to isolate and characterize intermediate precursor cell states, much of the current
understanding of the mouse and human Sec lineages rests on mouse genetic studies. On morphologic and
functional grounds, the four mature Sec cell types are considered distinct and their origins trace to a common
ATOH1-expressing crypt progenitor (Sec-Pro), although some mouse EE and tuft –but not Gob or Pan– cells
arise in the absence of this Sec-specifying transcription factor (TF). Cell fates are generally dictated by cell-
specific cis-regulatory elements (CREs – mainly enhancers) that drive particular transcriptional programs
under the direction of cell-restricted TFs. To understand how primitive Sec-Pro execute subsequent CRE
and cell fate decisions, we have developed two parallel and powerful experimental systems: (1) Capture of
labeled early mouse Sec derivatives in vivo for deep characterization of gene and enhancer activity at single-
cell resolution, and (2) Differentiation of 2D human ISC-like cells in vitro along the full Sec lineage. Both
models yield large numbers of multi- and bi-potential precursors, hence allowing original mechanistic insights
into the corresponding transcriptional and CRE states. Our three Specific Aims integrate findings from the
two parallel models to decipher the epigenetic basis and regulatory TF logic of mouse and human Sec cell
differentiation. Aim 1 uses mRNA and open-chromatin profiles of precursor and descendant Sec cells within
a differentiation continuum to characterize the salient features of specific intermediate states, map previously
unknown TF-driven transitions, distinguish cell-autonomous from -extrinsic factors, and thus derive a unifying
model for mammalian Sec lineage diversity. Considered in the light of scattered published findings, our
preliminary data suggest that Gob and Pan are not genuinely distinct cell types, but different versions of a
versatile Sec end-product where specific local signals act on the same complement of open chromatin to
drive Gob or Pan features. Aim 2 applies a suite of in vitro and in vivo experiments to test specific hypotheses
that epidermal growth factor (EGF) and especially canonical Wnt signaling favor the Pan state, while bone
morphogenetic protein (BMP) signaling drives the Gob state. We will examine how alternative recruitment of
Gob- or Pan-selective CREs by specific signaling pathways might underlie these fluid cell states. Aim 3 uses
gain- and loss-of-function strategies to address previously challenging questions about TF-driven
specification of human Sec, especially EE and tuft, cells. Overall, a particular stren...

## Key facts

- **NIH application ID:** 10793613
- **Project number:** 5R01DK082889-12
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Ramesh A Shivdasani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $357,716
- **Award type:** 5
- **Project period:** 2010-09-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10793613

## Citation

> US National Institutes of Health, RePORTER application 10793613, Transcriptional control and enhancer recruitment in mouse and human intestinal secretory differentiation (5R01DK082889-12). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10793613. Licensed CC0.

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