# Molecular Mechanism of TET-mediated Gene Regulation

> **NIH NIH R35** · OHIO STATE UNIVERSITY · 2024 · $383,265

## Abstract

PROJECT SUMMARY/ABSTRACT
DNA cytosine methylation is a central epigenetic modification in mammalian cells. Aberrant DNA methylation
has been linked to gene dysregulation and genomic instability, resulting in cancer and other diseases. Ten-
Eleven Translocation (TET) is the essential enzyme family responsible for DNA demethylation to ensure the
proper maintenance of the methylome. TET enzymes oxidize 5-methylcytosines (5mC) into mainly 5-
hydroxymethylcytosine (5hmC), an intermediate for DNA demethylation and a potential epigenetic mark.
Germline deficiency of TET2 is associated with immunodeficiency and childhood cancers. Notably, TET2 is
one of the most frequently mutated genes in hematological cancers, demonstrating the importance of TET in
multiple biological processes. We and others have shown that TET enzymes are essential for cell
differentiation by regulating super-enhancers and inducing the expression of lineage-specific genes. However,
the mechanism by which TET enzymes facilitate the permissive chromatin environment for gene activation
remains unclear. The long-term goals of the research program are: (1) to comprehensively understand how
TET enzymes and 5hmC promote chromatin accessibility; (2) to investigate the crosstalk between TET and
histones; (3) to understand the consequences of temporary perturbation of epigenome. To accomplish these
goals, we will use precision epigenome editing to manipulate and monitor epigenetic modifications of cis-
elements regulated by TET and DNA methylation. We will develop novel animal models to study the impact of
acute and reversible TET deficiency and a sequencing method to map multiple DNA modifications and
chromatin accessibility simultaneously on a single DNA molecule. Our research will provide crucial mechanistic
insights into how TET and DNA modifications regulate gene expression and cell differentiation. Our findings
will potentially identify genes involved in immunodeficiency and cancer, providing an opportunity to develop
targeted treatments.

## Key facts

- **NIH application ID:** 10907662
- **Project number:** 5R35GM151110-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Jerry Chan-Wang Lio
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $383,265
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907662

## Citation

> US National Institutes of Health, RePORTER application 10907662, Molecular Mechanism of TET-mediated Gene Regulation (5R35GM151110-02). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10907662. Licensed CC0.

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