A sex‐specific role for long noncoding RNA in depression susceptibility and resilience

Abstract

Major depressive disorder is a common, chronic, and debilitating disorder. Depression strikes women twice more than men, yet the molecular mechanisms contributing to this sex difference are poorly understood. Epigenetic processes that mediate interactions between genetic predispositions and stressful life experiences are known to play a critical role in depression risk. Here, we explored the roles of long noncoding RNAs (lncRNAs), a novel class of epigenetic regulators that are enriched in the primate brain, in depression in both sexes. To that end, we integrated cutting‐edge molecular, bioinformatics, behavioral, and physiological approaches spanning both humans and mice. We found that lncRNAs are robustly regulated in a sex‐specific manner in postmortem brain tissue from depressed humans compared to healthy controls. Utilizing a genome‐wide “guilt‐by‐association” bioinformatics approach, we identified sex‐specific lncRNAs linked to depression. One of these targets, LINC00473, is neuronal‐enriched and is specifically downregulated in the prefrontal cortex of depressed females only. To determine a causal role for LINC00473 in depression, we virally expressed it in mice of both sexes’ prefrontal cortex neurons followed by a behavioral examination. This manipulation mirrored the human sex‐specific phenotype, as expressing LINC00473 induced stress resilience in females only, which was accompanied by changes in synaptic function and gene expression. Another lncRNA we identified (RP11‐298D21.1) is upregulated in the depressed female brain, and therefore we named it FEDORA (FEmale DepressiOn lncRnA). FEDORA is expressed in oligodendrocytes and neurons; thus, we utilized a cell type‐specific viral expression system to test its role in both cell types. We found that expressing FEDORA promoted depression‐like behaviors only in female mice in both cell types. However, these behavioral changes were associated with cell‐type‐specific transcriptional changes, as well as altered electrophysiological and morphological features. Finally, we found that circulating FEDORA levels reflect its brain expression profile: blood FEDORA levels are elevated only in depressed women, suggesting FEDORA as a potential sex‐specific biomarker for a depression diagnosis. Together, this work establishes that lncRNAs play a key role in depression and contribute to the sex differences of this disorder. These findings provide a new view of molecular adaptations contributing to depression risk and point to promising targets for developing novel depression diagnosis and treatment tools.