Abstract
Major depressive disorder (MDD) is a multifaceted condition that is shaped by an interaction between genetic and environmental factors. Besides the changes at the neuroanatomical level and within brain circuits, how the brain's transcriptome is regulated plays a vital role in defining MDD pathogenesis. The progression of heterochromatic states is a hallmark of genome-wide silencing of transcriptional activity and has recently been linked to the disruption of gene functions in the brains of individuals with MDD. These genome-wide changes are often associated with altered three-dimensional (3D) chromatin structure, influenced by state-dependent factors including noncoding RNAs and associated enzymatic modifiers. Long noncoding RNAs (lncRNAs) have gained significant attention for their ability to regulate epitranscriptional processes, including 3D chromatin organization. Despite the recognized importance of these interactions, a knowledge gap persists in linking 3D chromatin architectural changes with lncRNA activity in the brains of individuals with MDD. This review explores the role of lncRNAs in the heterochromatinization process within the nuclear genome, particularly in the context of MDD, by examining their interaction with RNA-binding proteins (e.g., PRC2) and histone modifications (e.g., H3K4me3 and H3K27me3). By investigating these mechanisms, this review aims to shed light on how lncRNAs and related modifiers may influence gene expression programs in MDD, potentially revealing new therapeutic targets for this condition.