# Epigenetic regulation of neural stem cell biology by Tet DNA dioxygenases

> **NIH NIH F30** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2024 · $53,974

## Abstract

ABSTRACT
 The ten-eleven translocation family (TET1/2/3) of enzymes are epigenetic regulators of gene expression
that are highly expressed in neural stem cells (NSCs) and during mammalian nervous system development. TET
enzymes are dioxygenases that promote active and passive DNA demethylation by converting 5-methylcytosine
(5mC) into 5-hydroxymethycytosine (5hmC) and higher-order oxidized derivatives. In addition to its role as a
demethylation intermediate, 5hmC can function as a stable epigenetic mark and is highly enriched and dynamic
in the developing nervous system. TET enzymes and 5hmC dysregulation have been implicated in human
neurodevelopmental syndromes, intellectual disability, craniofacial abnormalities, and neurodegeneration.
These observations suggest a critical role for TET enzymes in the developing nervous system and has led to
interest in their roles in the biology of NSCs. However, the functions of TET enzymes in NSCs and
neurodevelopment remain poorly understood. Preliminary data from our lab demonstrates that Tet triple-
knockout NSCs (T123–/–) derived from embryonic stem cells exhibit severe defects in self-renewal, multipotency,
and expression of neurodevelopmental genes. We therefore hypothesize that TET enzymes have essential
functions in epigenetic regulation of gene expression programs critical for NSC maintenance and multipotency
and in embryonic neurodevelopment. To test this hypothesis, we have derived embryonic forebrain NSC lines
containing floxed alleles of Tet1/2/3 and a tamoxifen-inducible Cre recombinase transgene expressed from the
constitutive Rosa26 locus (T123F/F; +/R26-CreER) for conditional, combined deletion of all three Tet genes. We
have also established a colony of Tet1/2/3 triple-floxed mice expressing a tamoxifen-inducible Cre recombinase
transgene under control of the neural-specific Nestin promoter (T123F/F; +/Nestin-CreERT2). Using these models,
we will (1) define the role of TET enzymes in the maintenance and multipotency of NSCs , (2) establish the
requirement of TETs in embryonic neurodevelopment, and (3) identify TET-mediated epigenetic and
transcriptional regulatory mechanisms in NSCs. Findings from these studies will define novel roles played by
TET enzymes in NSC biology and neurodevelopment, provide insights into how dysregulation of TETs contribute
to human neurodevelopmental disorders, and identify novel targets for therapy. Under the joint mentorship of
Drs. Meelad Dawlaty and Jean Hébert, I will successfully execute the proposed research and training plan. This
research program will further my knowledge of the epigenetic regulation of neural stem cell biology and facilitate
my scientific and professional development by equipping me with the necessary skills to become a physician-
scientist.

## Key facts

- **NIH application ID:** 10791766
- **Project number:** 5F30HD107921-03
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Ian Campbell MacArthur
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,974
- **Award type:** 5
- **Project period:** 2022-02-09 → 2026-02-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10791766

## Citation

> US National Institutes of Health, RePORTER application 10791766, Epigenetic regulation of neural stem cell biology by Tet DNA dioxygenases (5F30HD107921-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10791766. Licensed CC0.

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