# Determining the role of Tet1 in facultative intestinal stem cells

> **NIH NIH F31** · EMORY UNIVERSITY · 2023 · $47,694

## Abstract

PROJECT SUMMARY
Active intestinal stem cells (aISCs) are tasked with maintaining the highly proliferative intestinal epithelium, a
tissue with absorptive, secretory, and barrier functions that are critical to homeostasis and survival. Dysregulation
of aISCs can lead to inflammation and cancer, while loss of aISCs due to cytotoxic, pathogenic, or radiation-
induced injury can threaten epithelial integrity and pose a severe health risk. aISC injury is a common side effect
of chemotherapeutic or radiation treatment of cancer. In response to aISC injury, the intestinal epithelium has
the remarkable capacity to regenerate its stem cell pool through dedifferentiation of mature epithelial cells and
their progenitors, which function as facultative ISCs (fISCs). However, little is understood about the genetic
mechanisms that permit this high level of cellular plasticity. One way cells are able to simultaneously modulate
the expression of many genes is through chromatin modification. Ten-eleven translocation methylcytosine
dioxygenases (TET enzymes) are involved in DNA demethylation through the conversion of 5-methylcytosine
(5mC) to 5-hydroxymethylcytosine (5hmC), a process associated with gene activation. TET enzymes have well-
known functions in maintaining stem cell-specific gene expression in mouse embryonic stem cells, and published
data from our lab demonstrate that Tet1 is enriched in adult mouse ISCs and intestinal epithelial progenitors. My
preliminary data show that the loss of Tet1 results in aberrant lineage specification, suggesting a central role for
Tet1 in changing cell identity. The central hypothesis of this proposal is that Tet1 facilitates ISC identity
transitions through activation of cell type specific gene expression. I will test this hypothesis with the
following specific aims: Aim 1 will establish the genetic requirement for Tet1 during fISC dedifferentiation
following aISC injury using both targeted aISC ablation and cytotoxic injury models. Post-injury regeneration will
be assessed by histology and organoid growth assays. Aim 2A will characterize Tet1’s gene regulatory
mechanisms during differentiation through genomic, epigenomic, and transcriptomic analysis of inducible Tet1
knockout (Tet1iKO) mice. Aim 2B will use the same approaches to describe Tet1’s gene regulatory mechanisms
during dedifferentiation in Tet1iKO mice that have suffered ISC injury. This project will determine how Tet1
facilitates changes in cell identity and provide me with training towards my goal of obtaining a research-focused
faculty position studying chromatin regulatory mechanisms of maintaining stem cell function and establishing cell
identity. This work will advance the understanding of regenerative mechanisms and provide insight into intestinal
epithelial responses to damage and injury.

## Key facts

- **NIH application ID:** 10678519
- **Project number:** 1F31DK136254-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** NICOLAS VAUGHAN JANTO
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $47,694
- **Award type:** 1
- **Project period:** 2023-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10678519

## Citation

> US National Institutes of Health, RePORTER application 10678519, Determining the role of Tet1 in facultative intestinal stem cells (1F31DK136254-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10678519. Licensed CC0.

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