# MECHANISMS OF EPIGENETIC REGULATION IN NERVOUS SYSTEM DEVELOPMENT

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $393,229

## Abstract

Abstract Advances in human genetics have led to the identification of a large number of genes associated with
autism spectrum disorder (ASD), intellectual disability (ID), and related neurodevelopmental diseases. A critical new
challenge is to understand the molecular pathways these genes contribute to in neurons and to dissect how their
disruption alters nervous system function. Methylation of cytosines in DNA classically occurs only at CG
dinucleotides, but recent studies have also uncovered functions for unique non-CpG DNA methylation in neurons
(which occur largely at CA dinucleotides, mCA). We have discovered that the methyl-DNA-binding protein MeCP2,
which is critical for proper nervous system function, binds to mCA within the transcribed regions of genes in
neurons to downregulate their expression. New studies have identified mutations in DNMT3A, the DNA
methyltransferase required for the deposition of mCA in the brain, in individuals with ID and ASD. These findings
support the hypothesis that disruption of gene regulation mediated by mCA contributes to disorders caused by
mutation of DNMT3A. Our proposed studies will test this hypothesis by pursuing three specific aims: Aim 1 will use
in vitro cell culture systems to determine how disease-associated mutations in DNMT3A affect enzyme function and
alter deposition of mCA in neurons. Aim 2 will employ newly-generated transgenic mice carrying heterozygous
mutations in DNMT3A to determine the effects of this disruption on neuronal DNA methylation, chromatin structure,
transcription and cellular functions. Aim 3 will interrogate the mechanisms by which mCA and MeCP2 directly
regulate transcription in neurons, testing the hypothesis that these components interact with novel gene-regulatory
sites to control transcription. Together these studies will determine the molecular mechanisms by which mCA
regulates gene expression in neurons, and define a site of molecular pathology in ASD and ID.

## Key facts

- **NIH application ID:** 9893903
- **Project number:** 5R01MH117405-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Harrison W Gabel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $393,229
- **Award type:** 5
- **Project period:** 2019-03-14 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893903

## Citation

> US National Institutes of Health, RePORTER application 9893903, MECHANISMS OF EPIGENETIC REGULATION IN NERVOUS SYSTEM DEVELOPMENT (5R01MH117405-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9893903. Licensed CC0.

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