# Epigenetic regulation of stem cells and development by the DNA dioxygenase Tet2

> **NIH NIH F31** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2022 · $51,752

## Abstract

ABSTRACT
 The Ten-eleven translocation (Tet1/2/3) family of enzymes are epigenetic regulators of gene expression
important for stem cell biology and embryonic development. Tet enzymes are dioxygenases that promote DNA
demethylation by converting 5-methylcytosine (5mC) into 5-hydroxymethycytosine (5hmC) and higher oxidized
derivatives. In addition to this enzymatic activity, Tet enzymes can bind chromatin modifying complexes, to
regulate genes in a presumably catalytic-independent manner. Tet2 is a key member of this family. It is highly
expressed in embryonic stem cells (ESCs) and controls gene expression programs necessary for stem cell
lineage specification. Tet2 is also frequently mutated in hematological malignancies and has been implicated in
neurodegenerative diseases. While the catalytic functions of Tet2 have been well studied, its non-catalytic roles
remain poorly defined. In this proposal, we seek to establish the significance of the catalytic dependent and
independent functions of Tet2 in ESC gene regulation and lineage commitment. We hypothesize that Tet2, in
addition to regulating genes through its DNA demethylase activity, can also modulate genes in a non-catalytic
fashion by recruiting histone modifiers to the chromatin, and this dual mode of gene regulation is essential for
proper ESC differentiation along the neural and hematopoietic lineages. To test this hypothesis, I have generated
Tet2 catalytic mutant (Tet2m/m) and knock-out (Tet2–/–) ESCs, which I will use as a platform to: (1) identify the
catalytic and non-catalytic direct target genes of Tet2 in ESCs by integrating changes in gene expression with
Tet2 genomic occupancy, (2) establish Tet2-mediated activating and repressing mechanisms of gene regulation
involving interactions with histone modifiers OGT and HDAC2, and finally (3) define the biological significance
of Tet2 enzymatic and non-enzymatic functions in ESC differentiation and lineage commitment along the neural
and hematopoietic lineages. Findings from these experiments will elucidate novel epigenetic mechanisms of
gene regulation in ESCs involving Tet2 catalytic and non-catalytic functions. They will enhance our
understanding of stem cell biology and development and can have implications in hematological malignancies
where Tet2 is affected. Under the combined mentorship of Drs. Meelad Dawlaty and Bernice Morrow, I will
successfully execute the proposed research and training plans. This will allow me to contribute greatly to the
fields of epigenetics and stem cell biology and develop the necessary research, professional and interpersonal
skills to become and independent physician-scientist investigator.

## Key facts

- **NIH application ID:** 10348168
- **Project number:** 5F31GM140554-02
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Julio C Flores
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 5
- **Project period:** 2021-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348168

## Citation

> US National Institutes of Health, RePORTER application 10348168, Epigenetic regulation of stem cells and development by the DNA dioxygenase Tet2 (5F31GM140554-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10348168. Licensed CC0.

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