# Neuron subtype specific role of DNA methylcytosine dioxygenase TET1 in cocaine addiction

> **NIH NIH R01** · FLORIDA STATE UNIVERSITY · 2021 · $340,935

## Abstract

Neural function requires accurate control of gene transcription in response to environmental stimuli.
Epigenetics plays a crucial role in this process by modulating gene expression without changing underlying
DNA sequences. DNA methylation is a major epigenetic mechanism, wherein a methyl group is covalently
coupled to the C5 position of cytosine, predominantly at 5'-CpG-3' dinucleotide sites. Though still few in
number, accumulating evidence demonstrates that DNA methylation may play important roles in drug
addiction. However, to firmly establish DNA methylation's role in drug addiction, the question of whether and
how DNA methylation changes take place and function in neurons must be addressed. This is particularly
true for those defined neuronal subtypes selectively engaged in drug addiction. To address this question,
we herein propose to study methylcytosine dioxygenase TET1, a newly identified DNA demethylation
enzyme, and its mediated DNA methylation turnover in the two major neuron types (D1- and D2- medium
spiny neurons (MSNs)) in nucleus accumbens in cocaine addiction. In the past, we have found TET1, but
not TET2 or TET3 (the other two members of the dioxygenase family), is selectively regulated by cocaine in
the nucleus accumbens. We have also shown TET1 mediates drug reward behaviors. Here, we propose
TET1 carries distinct functions in D1- and D2-MSNs, which usually play opposite roles in addiction reward
circuitry. We will also elucidate TET1-mediated neuron subtype-specific DNA methylation changes in D1-
and D2-MSNs. Lastly, we will probe the long-standing question of the causal functional role of DNA
methylation in drug addiction-relevant behavior through a proven CRISPR-Cas9 based epigenome editing
approach to modify DNA methylation at selective loci. Upon completion, our study will not only advance our
scientific understanding of DNA epigenetic underpinnings of drug addiction in a neuron subtype-specific
manner, it will also provide a path to manipulate behaviors associated with drug addiction through cell type-
specific precision epigenome editing, which has obvious potential utility for future therapeutic applications.

## Key facts

- **NIH application ID:** 10177985
- **Project number:** 5R01DA046720-04
- **Recipient organization:** FLORIDA STATE UNIVERSITY
- **Principal Investigator:** Jian Feng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $340,935
- **Award type:** 5
- **Project period:** 2018-09-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10177985

## Citation

> US National Institutes of Health, RePORTER application 10177985, Neuron subtype specific role of DNA methylcytosine dioxygenase TET1 in cocaine addiction (5R01DA046720-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10177985. Licensed CC0.

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