# The role of H3K36 methyltransferases on non-CpG methylation patterning in the mammalian brain

> **NIH NIH F30** · WASHINGTON UNIVERSITY · 2022 · $32,686

## Abstract

Project Summary:
Human genetic studies have linked autism and related neurodevelopmental disorders (NDD) to disruption of
genes encoding epigenetic factors. While mutations in these genes can affect more than one pathway that leads
to ASD, identification of a common molecular pathway across genetic causes of ASD can provide insight into
broadly applicable therapies. Recent evidence from our laboratory suggests that a neuronal-specific form of DNA
methylation is a shared epigenetic modification that is disrupted in ASD-associated neurodevelopmental disease.
 Though DNA methylation is classically considered to only occur in mammalian cells in the CpG context,
neurons are uniquely enriched for methylation in non-CpG contexts established by DNMT3A. This non-CpG
methylation primarily occurs at CA dinucleotides (mCA) and is critical for proper neuronal development and
function. Though mCA plays an important role in regulating neuronal gene expression, it is not known how the
mCA landscape is faithfully established across the neuronal genome, and whether additional NDDs involve
disruption of mCA. Recent studies outside the nervous system have suggested that histone modifications may
play a central role in directing DNMT3A-mediated DNA methylation across the genome, but it is not known to
how these histone modifications influence DNMT3A and mCA throughout the neuronal genome.
 Intriguingly, mutations in H3K36 histone methyltransferases have been recently identified in ASD gene
studies. Additionally, recent studies conducted outside the nervous system have suggested that H3K36
methylation recruits DNMT3A and regulates its activity. In this proposal, I will determine how disruption of H3K36
methylation-mediated interactions with DNMT3A disturbs critical patterns of mCA across the neuronal genome
to drive brain dysfunction. In Aim 1, I will disrupt NDD-relevant H3K36 methyltransferases and measure how
DNMT3A recruitment and mCA are affected. This will define the mechanisms underlying histone and DNA
modification dynamics on regulating neuronal transcription and building our basic understanding of how
disruption of mCA drives disease. In Aim 2, I will explore how loss of H3K36 dimethylase NSD1 causes
dysregulation of neuronal genes via shared neuronal chromatin pathology observed across heterogenous clinical
syndromes of ASD. I will use genomic approaches to examine how altered DNA methylation as a result of NSD1
loss affects enhancer activity to drive transcriptional dysregulation in nervous system dysfunction and disease.
This analysis will begin to identify key downstream chromatin associated factors across a common molecular
pathway involved in multiple genetic causes of ASD to provide insight into functional cellular outcomes and
broadly applicable therapies.

## Key facts

- **NIH application ID:** 10535544
- **Project number:** 1F30HD110156-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Nicole Hamagami-Samson
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $32,686
- **Award type:** 1
- **Project period:** 2022-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10535544

## Citation

> US National Institutes of Health, RePORTER application 10535544, The role of H3K36 methyltransferases on non-CpG methylation patterning in the mammalian brain (1F30HD110156-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10535544. Licensed CC0.

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