Cell-Type-Specific Transcriptomic Signatures in Prefrontal Cortex Reveal lncRNA-mediated Gene Silencing and Enhancer Activities Contributing to the Pathophysiology of Major Depressive Disorder

Long non-coding RNAs (lncRNAs) have emerged as pivotal epigenetic regulators that influence chromatin structure, gene expression, and various cellular processes. We conducted a comprehensive transcriptomic analysis to explore the regulatory roles of lncRNAs in gene expression across major cell types. Based on the cell type abundance as predicted by CIBERSORTx, the gene expression deconvolution of lncRNAs and mRNAs obtained from nonpsychiatric control (n=41) and MDD (n=59) subjects was carried out using bMIND. LncRNA regulatory activity and functional enrichment analysis were assessed in each cell type. Interactions between lncRNAs and transcription factors and RNA-binding proteins, as well as their associations with DNA and RNA, were obtained from the RNA Interactome Database. The protein-protein interactions of lncRNA-regulated mRNAs and the associations between genes and psychiatric disorders were sourced from STRING network PsyGeNET databases, respectively. We observed a prevalence of inhibitory neurons in the control group and a higher proportion of excitatory neurons within the MDD group. A significant dysregulation of lncRNAs and mRNAs, characterized by distinct gene-silencing activity of lncRNAs, was observed, potentially facilitated through chromatin modifications in excitatory and inhibitory neurons, as well as enhancer activity of specific lncRNAs in both neuronal and glial cell types. Functional analyses of the silenced neuronal genes highlighted the involvement of cell adhesion molecules and stress-related signaling in MDD, indicating disrupted neuron-glia interactions. The enhancer activity of lncRNAs indicated the positive regulation of genes involved in Hippo signaling and neurodegeneration. This work uniquely highlights the cell-type-specific roles of lncRNAs and their contributions to MDD pathophysiology. HIGHLIGHTSO_LIComprehensive cell-type-specific transcriptomic analysis of dorsolateral prefrontal cortex in MDD subjects. C_LIO_LIDistinct gene-silencing activity of lncRNAs in excitatory and inhibitory neurons. C_LIO_LIEnhancer activity of specific lncRNAs in both neuronal and glial cell types. C_LIO_LICritical roles of lncRNAs and associated cellular functions in the pathophysiology of MDD. C_LI