# Epigenetic roles of DNA adenine methylation in stress response

> **NIH NIH R01** · EMORY UNIVERSITY · 2022 · $390,272

## Abstract

Project Summary
Methylation on the DNA adenine, N6-methyladenine (6mA) that enriched in the bacteria genome, was recently
found in the Drosophila and mammalian genomes. 6mA is dynamically regulated during embryonic development
and could play epigenetic roles in regulating gene and transposon expression. However, the roles of 6mA in
mammalian brains remain largely unknown. Our preliminary study highlights that 6mA, and its molecular
machinery, is required for proper neurodevelopment in Drosophila brains. Preliminary data consistently
demonstrated a dynamic regulation of 6mA during postnatal mouse brain and human embryoid body
development. Environmental chronic stress induces dynamic alteration of 6mA in mouse brains, in the loci highly
correlated with depression. The complex changes in postnatal brain development due to the epigenetic alteration
could account for the altered stress response and many mental illnesses, the molecular mechanisms connecting
these processes remain unclear. The involvement of 6mA and its putative machinery in brain development and
stress response makes them an attractive causal mechanism in these connected processes. However, there is
little research precisely examining the brain region-specific and neuronal cell type-specific 6mA dynamics and
their epigenetic roles during brain development. Furthermore, the lack of knowledge regarding the 6mA
methyltransferases (“writers”) and its binding proteins (“readers”) in the mammalian genome hinders our further
understanding of their precise epigenetic roles in brain development and stress response. Based on this work,
we hypothesize that 6mA and its molecular machinery play crucial roles in mammalian brain development, and
their dysregulation contributes to altered stress response in the brain. We will first use established genome-wide
6mA mapping tools to identify brain region-specific and cell type-specific differentially 6mA methylated regions
(D6AMRs) during mouse postnatal development and correlate these data with global transcriptome analysis to
pinpoint the detailed and precise epigenetic roles of 6mA in these processes (Aim 1). We will then define 6mA
putative methyltransferases “writers” in the mammalian genome and modulate their expression in vivo to test
their roles in development-related stress response through 6mA regulation in excitatory and inhibitory neurons
(Aim 2). Our data suggest 6mA could potentially antagonize or recruit hypoxia-induced factor-1 (Hif1) and
Drosophila Polycomb (Pc), respectively. Based on these results, we will determine the interplay of Hif1 and
mammalian Polycomb proteins with 6mA and their roles in development-related stress response at the neuronal
levels as well (Aim 3). Findings of this study will provide novel mechanistic insights of 6mA in brain development
and its related stress response and are likely to discover new molecular targets with important clinical and
translational implications in mental illnesses.

## Key facts

- **NIH application ID:** 10323656
- **Project number:** 5R01MH117122-04
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Bing Yao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $390,272
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10323656

## Citation

> US National Institutes of Health, RePORTER application 10323656, Epigenetic roles of DNA adenine methylation in stress response (5R01MH117122-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10323656. Licensed CC0.

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