Aberrant expression of long non-coding RNAs and their regulatory role in chromatin-mediated gene expression changes in the prefrontal cortex of major depressive disorder subjects

Long non-coding RNAs (lncRNAs) have emerged as critical regulators of gene expression, particularly in complex neuropsychiatric disorders such as major depressive disorder (MDD). This study investigates the expression of lncRNAs in the dorsolateral prefrontal cortex (dlPFC) of MDD subjects and their potential roles in chromatin remodeling and gene silencing. Following the 8×60 K microarray platform, we profiled the expression of 35,003 lncRNAs in 59 MDD and 41 control subjects, identifying 1625 upregulated and 1439 downregulated lncRNAs in the MDD group. Co-expression network analysis revealed a complex and interconnected lncRNA network in MDD, suggesting intricate regulatory mechanisms. Furthermore, by employing the PIRCh-seq technique, we found that a subset of 60 upregulated lncRNAs in the MDD brain interacts with heterochromatic regions marked by the H3K27me3 modification, thereby silencing gene expression. These lncRNAs were associated with 24 downregulated protein-coding genes linked to neuronal functions, including synaptic vesicle exocytosis and neurotransmitter release. Gene ontology and pathway analyses highlighted disruptions in critical neurobiological functions, with particular emphasis on synaptic and neuronal signaling pathways. Our findings underscore the role of lncRNA-mediated heterochromatization in the pathophysiology of MDD, offering novel insights into the epigenetic regulation of brain function and behavior.