# TET-mediated DNA oxidations in mucosal innate defense

> **NIH NIH R21** · RUTGERS THE STATE UNIV OF NJ NEWARK · 2022 · $235,500

## Abstract

PROJECT SUMMARY
DNA methylation pattern in the genome of intestinal epithelial cells (IECs) can be altered by gut microbiota. How
the functions of various IEC types are affected by such epigenetic changes under homeostatic and stress
conditions remain unclear. DNA methylation is a repressive epigenetic mark that can be actively reversed by the
Ten-Eleven Translocation family of enzymes TET1, TET2 and TET3. TETs are DNA dioxygenases that
successively oxidize methylated DNA - 5-methylcytosine (5mC) - into 5-hydroxy-methylcytosine (5hmC), 5-
formylcytosine (5fC), and 5-carboxylcytosine (5caC). Both 5fC and 5caC can be excised by DNA based excision
repair factors leading to unmodified cytosines. TET enzymes were recently implicated as new risk factors in
inflammatory bowel disease (IBD) patients, but the role of TET-mediated DNA oxidation in homeostasis and in
response to environmental stressors are unknown. Preliminary data show that human IECs display an elevation
of 5hmC DNA oxidation upon infection by invasive pathogen, and mouse IECs lacking Tet3 had reduction of
5hmC abundance in ileal IECs. scRNA-Seq suggests that mouse Tet3 is the most abundant TET enzyme in
IECs, especially in Paneth cells. Tet3DIEC mice had reduced mature Paneth cells, increased susceptibilities to
inflammation caused by enteric pathogen or barrier-disrupting chemical. The project tests a central hypothesis
that TET3-mediated DNA oxidations play dual roles in guiding IEC differentiation and promoting anti-microbial
response via 5hmC-induced permissive chromatin while restraining differentiation via 5fC- and 5caC-induced
transcriptional pausing. Aim 1 will use genome wide approaches to identify intestinal stem cell (ISC) and Paneth
cell specific TET3 and DNA oxidation gene regulatory networks under homeostasis and in responding to distinct
cellular stressors such as pathogen and chemical. Aim 2 will characterize how ISC and Paneth cell specific
TET3-mediated DNA oxidation regulate mucosal inflammatory response. This MPI project, utilizing
complementary expertise in epigenetics and intestinal biology to address how DNA oxidations regulate the
epigenome in response to stressors to help resolve inflammation. The idea that TET-mediated DNA oxidations
may be an integral mucosal innate immune component to cope with oxidative stresses during infection and
inflammation is novel. Elucidating TET functions in specific IEC types may exert major impact on human
gastrointestinal mucosal immunology and diseases. If TET enzymes are indeed uncovered by this research as
key mediator and regulator of inflammatory responses, as predicted by literature and our preliminary data, the
outcome can be of high relevance to translational medicine.

## Key facts

- **NIH application ID:** 10525407
- **Project number:** 1R21AI167079-01A1
- **Recipient organization:** RUTGERS THE STATE UNIV OF NJ NEWARK
- **Principal Investigator:** Jean-Pierre Etchegaray
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $235,500
- **Award type:** 1
- **Project period:** 2022-06-07 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10525407

## Citation

> US National Institutes of Health, RePORTER application 10525407, TET-mediated DNA oxidations in mucosal innate defense (1R21AI167079-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10525407. Licensed CC0.

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