# Epitranscriptomic Mapping of Novel N6-Adenosine-based RNA Methylation in MDD Brain

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $592,303

## Abstract

Major depressive disorder (MDD) currently remains one of the leading causes of global disability. Despite the
rise in treatment options, remission rates in MDD patients are very low. Thus, there is critical need to identify the
biological substrates that precipitate in MDD in order to develop effective therapy. It is widely known that MDD
involves short- and long-term maladaptive processes to external stimuli, impairing the ability of individuals to
appropriately interact with the environment. So far, there is no coherent hypothesis that can fully explain this
phenomenon. Increasing evidence suggests that fine-tuning of transcriptional regulation by gene-environment
interaction is central to the etiology of MDD. In this regard, a paradigm shifting phenomenon has recently been
introduced with the unique concept of post-transcriptional gene regulation through epitranscriptomic mechanism
(most prominently being N6-methyladenosine [m6A]) which is not only involved in the regulation of transcript
abundance but has the profound ability to impact maturity, stability, localization, and most importantly, availability
of “select” gene transcripts to protein translation despite varying transcription rates in a highly “dynamic” and
“reversible” fashion. This mechanism facilitates quick response to external stimuli, fine-tunes protein
accessibility, and executes localized control, which is critical to stimulus-adaptive gene expression. Their roles
have recently been shown in synaptic plasticity as well as in the stress coping behavior of mice. Our own
preliminary data demonstrate that not only is m6A mRNA methylation machinery differentially expressed in
various brain areas, but their expression and functions in manipulating m6A methylation and subsequent
expression of specific transcripts are aberrant in the MDD brain. This has led us to propose an overarching
hypothesis that m6A methylation-based epitranscriptomic modification of mRNAs may act as a dynamic regulator
of a subset of genes in a brain region specific manner, which, by affecting specific molecular pathways in a
coordinated fashion, will participate in MDD pathogenesis. To test this, in dlPFC and hippocampus from healthy
controls and well-matched MDD subjects, we propose the following aims: 1) Examine whether MDD is associated
with differential regulation of m6A methylation machinery and distinctive m6A methylation profile at the
epitranscriptomic level in brain region specific manner; 2) Define MDD associated role of YTH family of reader
proteins in epitranscriptomic turnover of protein coding genes; 3) Examine the impact of m6A mRNA methylation
on dendritic availability of local epitranscriptomic pool and their contribution to MDD pathogenesis. By using
highly innovative molecular approaches, by precisely identifying the fate of the transcripts in translatable and
non-translatable pools mediated through specific m6A reader proteins, by examining the role of m6A methylation
at the synapse, and b...

## Key facts

- **NIH application ID:** 10148818
- **Project number:** 5R01MH118884-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Yogesh Dwivedi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $592,303
- **Award type:** 5
- **Project period:** 2019-07-16 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148818

## Citation

> US National Institutes of Health, RePORTER application 10148818, Epitranscriptomic Mapping of Novel N6-Adenosine-based RNA Methylation in MDD Brain (5R01MH118884-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10148818. Licensed CC0.

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