Altered m6A RNA methylation profiles in depression implicate the dysregulation of discrete cellular functions in males and females

Adverse environmental stress represents a significant risk factor for major depressive disorder (MDD), often resulting in disrupted synaptic connectivity which is known to be partly regulated by epigenetic mechanisms. N⁶-methyladenosine (m6A), an epitranscriptomic modification, has emerged as a crucial regulator of activity-dependent gene regulation. In this study, we characterized m6A profiles in the ventromedial prefrontal cortex (vmPFC) of individuals with MDD. Using m6A sequencing, we identified a total of 30,279 high-confidence m6A peaks, exhibiting significant enrichment in genes related to neuronal and synaptic function. The m6A peaks between males and females with MDD that passed the significance threshold showed opposite m6A patterns, while the threshold-free m6A patterns were concordant. Distinct m6A profiles were found in MDD for each sex, with dysregulation associated with microtubule movement in males and neuronal projection in females. Our results suggest the potential roles of m6A as part of the dysregulated molecular network in MDD.