LSD1 splicing is regulated by the long non-coding RNA MALAT1 and orchestrates stress resilience in mammals

Abstract Psychiatric disorders often arise from the interaction between genetic predisposition and chronic psychosocial stress, yet the molecular programs determining resilience versus susceptibility remain incompletely understood. Building on evidence that the transcriptional corepressor LSD1 links environmental stress to neuronal gene regulation, we investigated whether isoform-specific regulation of LSD1 splicing contributes to stress adaptation. Using a mouse model of chronic social defeat stress, we analyzed LSD1 microexon E8a splicing in the hippocampus of resilient and susceptible animals. RNA-seq was performed after the last stress session to capture genome-wide transcriptional responses during the window of LSD1 splicing regulation. Comparative analyses with published LSD1 knockdown, LSD1 ChIP-seq and chronic stress datasets were conducted. Hippocampal samples from suicide victims were analyzed to assess translational relevance. Analysis of LSD1 splicing dynamics revealed that resilient mice, but not susceptible animals, retained the ability to reiterate acute stress-induced exon E8a skipping after repeated stress exposure, preserving the capacity to upregulate the enzymatically active ubLSD1 isoform in the hippocampus. In susceptible mice this inducible splicing response was absent. Mechanistically, splicing regulation involved the long non-coding RNA MALAT1, which controls the neurospecific splicing factor nSR100, a regulator of LSD1 exon E8a inclusion. Reduced MALAT1 expression in susceptible mice coincided with marked overactivation of stress-responsive genes revealed by RNA-seq. Approximately 15% (86 of 595) of genes deregulated in susceptible versus resilient hippocampi overlapped with transcripts modulated by LSD1 knockdown in an independent neuronal system. Of these, 25 were direct LSD1 ChIP-seq targets. ESR1 emerged as a regionally divergent upstream regulator associated with susceptibility. The MALAT1–nSR100–LSD1 axis represents a regulatory pathway modulating stress adaptation. Downregulation of ubLSD1 and MALAT1 in the hippocampus of suicide victims recapitulates the molecular phenotype observed in stress-susceptible mice, linking disruption of this pathway to pathological behavioral outcomes.