Rewriting the brain: m6A RNA methylation as an emerging epitranscriptomic regulator in major depressive disorder
Year: 2026
Type: review
Abstract: Activity-dependent gene regulation is fundamental to synaptic plasticity, and its disruption is increasingly recognized as a feature of major depressive disorder (MDD). Environmentally driven changes in gene expression can alter neural plasticity in corticolimbic brain regions, yet the post-transcriptional mechanisms linking environmental stress to maladaptive neuronal function remain incompletely understood. RNA epitranscriptomic regulation has recently emerged as an important layer of gene control, with N6-methyladenosine (m6A) representing the most abundant and dynamically reversible internal modification of mammalian mRNA. Widely present in the adult brain, m6A regulates RNA splicing, export, stability, localization, and translation, thereby shaping transcript fate and protein output. Although m6A RNA methylation has been studied extensively in other biological contexts, its contribution to MDD pathophysiology is only beginning to be defined. Current human evidence is primarily correlative, derived largely from bulk-tissue postmortem datasets, and should be considered hypothesis-generating until replicated in independent cohorts and validated with cell-type-resolved and mechanistic approaches. Emerging clinical and preclinical studies suggest that dysregulated m6A signaling may influence neurodevelopmental, neurocognitive, and stress-responsive pathways relevant to depression. By integrating environmental signals with transcriptomic regulation, m6A modification may represent a plausible epitranscriptomic mechanism governing synaptic plasticity in the depressed brain. In this review, we summarize the dynamic regulation of m6A RNA methylation in the brain, discuss its neurobiological functions, and critically evaluate its potential role in stress-related pathology and MDD.
Institutions: University of Alabama at Birmingham, UAB Medicine
Language: English
Topic: RNA modifications and cancer
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
Awards: Epitranscriptomic Mapping of Novel N6-Adenosine-based RNA Methylation in MDD Brain, G2458790829, G3618992063, G6149264481, G6697359561, G6930204474, Plasma Exosomal MicroRNAs as Promising Novel Biomarkers for Suicidality and Treatment Outcome, Novel cell type-specific epigenetic role of nuclear lncRNAs in 3D heterochromatization and transcriptional repatterning in the MDD brain, MicroRNA Correlates of Childhood Maltreatment and Suicidality, Novel regulatory role of nuclear miRNAs in repatterning the transcriptional and post-transcriptional dynamics in MDD brain, Neural-Derived Plasma Exosomal MicroRNAs As Promising Novel Biomarkers for Suicidality and Treatment Outcome in Adolescents
OpenAlex ID: W7204520155