MALAT1–nSR100–LSD1: a conserved regulatory axis controlling stress adaptation

Psychiatric disorders often emerge from the interaction between genetic vulnerability and chronic stress, yet the molecular programs that govern resilience versus susceptibility remain poorly defined. Building on previous evidence identifying LSD1 as an epigenetic interface between environmental stress and neuronal gene expression, we identify LSD1 exon E8a splicing as a key determinant of stress adaptation. In a mouse model of chronic social defeat stress, resilient individuals selectively maintain the upregulation of the enzymatically active ubLSD1 isoform (skipping the microexon E8a) chronically reiterating the acute stress response. We further demonstrate that LSD1 splicing modulation in response to stress is controlled by the long non-coding RNA MALAT1 through its regulation of the neuron-specific splicing factor nSR100, master regulator of LSD1 exon E8a inclusion. Within the temporal window of ubLSD1 induction in the hippocampus of resilient animals, RNA-seq analysis revealed a previously unrecognized susceptible (SUS)-specific LSD1-related runaway transcription of stress-responsive genes. Finally, we show that both ubLSD1 and MALAT1 are downregulated in the hippocampi of suicide victims, closely mirroring the molecular phenotype observed in SUS mice. Together, these findings define a conserved MALAT1–nSR100–LSD1 regulatory axis as a critical modulator of stress adaptation, with direct implications for the pathophysiology and potential therapeutic targeting of stress-related psychiatric disorders.