Deciphering the epigenetic role of long non-coding RNAs in mood disorders: Focus on human brain studies

Epigenetics plays a central role in neuropsychiatric disorders, contributing significantly to their complexity and manifestation. Major depressive disorder (MDD) and bipolar disorder (BD) have profound impact on mood, affect and cognition. Emerging evidence suggests that epigenetic modification of genes plays a pivotal role in the pathogenesis of both MDD and BD. Long non-coding RNAs (lncRNA) constitute a heterogeneous class of transcripts and have emerged as crucial regulators of epigenetic processes, offering promising insights into the pathophysiology of various diseases. Despite their limited coding potential, lncRNAs are known to play a critical role in achieving global transcriptomic regulation in a spatiotemporal fashion, especially in complex tissue like the brain. This review aims to discuss the specific dysregulation of lncRNAs so far observed in the brains of MDD and BD patients and understand their mechanistic contributions to the disease pathogenesis. KEY POINTS: Brain-centric lncRNAs regulate gene networks, and their disruption is linked to MDD. In MDD, altered lncRNAs disrupt gene regulation by changing chromatin looping or modifying chromatin accessibility. These changes lead to neuronal dysfunction, affecting neural circuitry and synaptic plasticity. The result is impaired brain function, contributing to the symptoms of MDD.