Aberrant MicroRNA-124 expression and methylation in the dorsolateral prefrontal cortex of depressed subjects

Major depressive disorder (MDD) is a prevalent psychiatric illness and a leading cause of suicide. Genetics and epigenetics play crucial roles in MDD pathogenesis. Among the epigenetic regulators, microRNAs (miRNAs) have gained significant attention for their ability to modulate gene expression post-transcriptionally, making them promising therapeutic targets. Previous research from our group identified brain-enriched miR-124-3p as a key regulator of MDD by targeting the glucocorticoid receptor, a crucial mediator of stress responses. However, the precise regulation of miR-124-3p in MDD, including its potential gender-specific expression patterns, remains unclear. This study aimed to investigate the role of miR-124-3p in MDD by addressing whether: 1) miR-124-3p expression is dysregulated in MDD subjects, 2) epigenetic modifications, particularly DNA methylation, contribute to this dysregulation, and 3) these changes are gender-specific. To test these, we replicated our previous findings by analyzing miR-124-3p expression in a cohort of dorsolateral prefrontal cortex samples from MDD (n = 25) and non-psychiatric control subjects (n = 30). Next, we assessed DNA methylation in the promoter regions of two miR-124-3p precursor genes using a methylated DNA immunoprecipitation assay. Our findings confirmed a significant upregulation of miR-124-3p in the PFC in MDD. Furthermore, we identified a significant reduction in DNA methylation in one of the miR-124 promoter regions on chromosome 20 in MDD subjects. Our results provide new insights into the epigenetic regulation of miR-124-3p in the brains of MDD subjects and highlight its potential role in MDD pathophysiology.