A new Genomic Psychiatry High-Priority Research Communication by Professor Yogesh Dwivedi and colleagues at the University of Alabama at Birmingham reports original, peer-reviewed findings demonstrating that long noncoding RNAs (lncRNAs) participate in stress-linked chromatin silencing during glucocorticoid receptor (GR) activation. Using an in vitro neuronal model, the team identified 79 significantly altered lncRNAs (44 upregulated, 35 downregulated; p < 0.05) following GR overexpression, with several physically interacting with the polycomb repressive complex 2 (PRC2) via EZH2 and the histone mark H3K27me3. These lncRNAs inversely correlated with nearby gene expression (R = –0.21, p < 0.005), repressing genes essential for synaptic communication and neuronal signaling. The discovery offers a mechanistic link between chronic stress exposure and long-lasting gene repression, suggesting that lncRNAs could serve as molecular signatures or intervention targets in major depressive disorder.