EXTENDING MALAT1 ACTIVITY TO THE MODULATION OF LSD1 SPLICING: A NOVEL MECHANISM DEVOTED TO STRESS RESILIENCY

The brain acts as the key central hub for detecting of environmental stress and triggering adaptive responses to manage threats. Among these mechanisms, the epigenetic spatiotemporal regulation of gene expression plays a pivotal role maintaining homeostasis by functionally restraining excessive neuronal excitability. Among the players, Lysine Specific Demethylase 1 (LSD1ub) plays a crucial role in repressing the expression of plasticity genes as a secondary stress response. Notably, its increased expression and activity in response to stimulation, are mediated by a transient reduction in the inclusion of its alternative exon E8a, leading to decreased levels of its dominant-negative splicing isoform, neuroLSD1. Understanding the mechanisms of LSD1 alternative splicing is essential, given the importance of the LSD1ub/neuroLSD1 ratio in stress responses and neuroplasticity. During my PhD research, I investigated the role of the lncRNA MALAT1 as an activity-dependent modulator of LSD1 splicing. Our data demonstrate that MALAT1 expression is increased in response to neuronal depolarization, both in vitro and in vivo, particularly upon stress exposure and developmental periods characterized by intense neuroplasticity. Through experiments involving MALAT1 overexpression and pharmacological inhibition, I observed that MALAT1 activity reduces the expression of neuroLSD1 in favor of LSD1ub upon depolarization. Additionally, cross-linking immunoprecipitation (CLIP) experiments suggest that MALAT1 interact with nSR100, the master splicing regulator of LSD1, potentially mediating its sequestration in inactive nuclear compartments. The correct functioning of homeostatic mechanisms, possibly including the splicing modulation of LSD1, is necessary for effectively terminating stress responses and establishing of adaptive behaviors. Chronic stress challenges these mechanism, creating potential hotspots for maladaptive behaviors and for the onset of psychiatric conditions. In this context, we propose LSD1ub and MALAT1 as novel stress-vulnerability genes. Our findings reveal that in the hippocampus of stress-susceptible mice, MALAT1 is downregulated alongside a deficiency in LSD1ub upregulation. Remarkably, this molecular signature is also observed in the hippocampus of individuals who died by suicide, an extreme manifestation of the stress response spectrum and depressive phenotype. Here, we identified reduced MALAT1 levels, which correlates with reduced LSD1ub expression compared to control individuals. Taken together, this research highlights the role of the novel MALAT1-nSR100-LSD1 pathway in the homeostatic control of stress responses, influencing resilient and adaptive behaviors, and suggesting that these genes are promising candidates involved in genetic stress vulnerability.