# MECHANISMS OF EPIGENETIC REGULATION IN NERVOUS SYSTEM DEVELOPMENT

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $655,201

## Abstract

PROJECT SUMMARY
With the identification of hundreds of genes associated with autism spectrum and related neurodevelopmental
disorders (ASD/NDD), there is a pressing need to define the molecular pathways these genes contribute to in the
nervous system and to dissect how their disruption alters brain function to drive disease. Methylation of cytosines in
DNA classically occurs at CG dinucleotides in mammalian cells, serving as an epigenetic mark often associated with
gene repression. However, a unique form of non-CG DNA methylation that occurs primarily at CA dinucleotides
(mCA) is highly enriched in neurons and has emerged as an essential regulatory modification needed to tune
neuronal transcriptomes. Notably, this DNA mark is susceptible to disruption due to mutation of the ASD/NDD gene
DNMT3A, as well as the Rett syndrome methyl-DNA-binding protein MeCP2, suggesting that the specialized
neuronal DNA methylation pathway may be vulnerable to disruption across additional causes of ASD/NDD. In recent
studies, we have uncovered new mechanisms that govern the patterning of mCA in neurons and identified key
functional outputs for the neuronal DNA methylation pathway in regulating cell-type-specific transcriptomes. We have
shown that the histone H3 lysine 36 dimethyl mark (H3K36me2) is necessary for targeting DNMT3A to deposit mCA
and demonstrated that mutation of the ASD/NDD-associated gene, NSD1, disrupts this histone mark, leading to
altered neuronal DNA methylation. We have further uncovered evidence that mCA deposited by the NSD1-
H3K36me2-DNMT3A cascade is read out by MeCP2 in a cell-type specific manner to control expression of genes
that define neuronal subtype-specific transcriptomes. In our proposed studies we will build on these findings to
investigate the mechanisms of DNMT3A targeting by H3K36me2 and assess their potential disruption due to
additional genetic lesions in ASD/NDD (Aim 1). We will then dissect the cell-type specific epigenetic consequences
of perturbing the NSD1-H3K36me2-DNMT3A cascade in NSD1 mutant mice (Aim 2). Finally, we will employ cutting-
edge spatial transcriptomic technologies to probe gene dysregulation caused by mutations in the neuronal DNA
methylation pathway across more than a hundred subtypes of neuronal and non-neuronal cells with single-cell spatial
resolution (Aim 3). Together these studies are significant because they will define new roles for ASD/NDD-associated
factors in the neuronal DNA methylation pathway and explore how disruption of these factors can alter neuronal
function. Furthermore, our implementation of spatial transcriptomic analysis for the study of ASD/NDD will provide
systematic understanding of the transcriptomic impacts caused by disease-associated mutations in this pathway at
the highest level of resolution.

## Key facts

- **NIH application ID:** 10804275
- **Project number:** 2R01MH117405-06
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Harrison W Gabel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $655,201
- **Award type:** 2
- **Project period:** 2019-03-14 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10804275

## Citation

> US National Institutes of Health, RePORTER application 10804275, MECHANISMS OF EPIGENETIC REGULATION IN NERVOUS SYSTEM DEVELOPMENT (2R01MH117405-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10804275. Licensed CC0.

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