PARTNERS, TARGETS AND MODULATORS OF LSD1 IN STRESS-RESPONSE REGULATION

In mammals, different forms of stress, including psychosocial stress, can affect various aspects of human health, promoting mood and anxiety disorders. However, very little is known about the mechanisms underlying the brain physiology of stress response, hindering the development of new therapeutic strategies. We uncover a role for the transcriptional corepressor Lysine Specific Demethylase-1 (LSD1) and its dominant negative splicing isoform neuroLSD1, in the modulation of emotional behavior. In the mouse hippocampus, LSD1 and neuroLSD1 interacting with the transcription factor Serum Response Factor (SRF) and SRFΔ5 participate as molecular transducers of stress stimuli. Likewise LSD1, also SRF is modulated by an alternative splicing isoform without transactivation domain, SRFΔ5. Psychosocial stress acutely reduces the expression of neuroLSD1 through a splicing-based modulation that results in an increase in the amount of LSD1, while the relative ratio between SRF and SRFΔ5 is sensitive both to ASDS and CSDS. Furthermore, SRFΔ5 shows SUS-restricted downregulation that might contribute to shaping psychosocial stress vulnerability, through interfering with homeostatic mechanisms underlying stress resiliency. All these data suggest the involvement of the dual LSD1/neuroLSD1 and SRF/SRFΔ5 in the adaptive response to stress. Alternative splicing is a strategic biological mechanism that allows to create a set of functionally different gene products from a single gene, diversifying gene functions without an increase in the number of genes. neuroLSD1, an activity-dependent splicing isoform that differs from LSD1 for the inclusion of exon 8a, was related to important homeostatic neuronal functions impacting emotional processing. It has recently been published that MALAT1(metastasis associated lung adenocarcinoma transcript 1), a long non-coding RNA, has a crucial role in the alternative splicing mechanism of some genes through the regulation of the splicing factor SRSF1, belonging to the SR protein family. In particular MALAT1 is mainly localized at the level of the nuclear speckles, where it seems to regulate the alternative splicing through the retention of SRSF1 in these nuclear domains and the modulation of their phosphorylation state through an unknown mechanism. We already published that alternative splicing involving LSD1 is positively regulated in trans by two splicing factors NOVA1 and nSR100. In particular, nSR100 is a splicing factor belonging to the SR protein family, as SRSF1, and regulates tissue-specific alternative splicing in a manner dependent on its concentration and its phosphorylation status. We propose MALAT1 as a negative modulator of the neurospecific splicing of LSD1, in particular following ASDS the increased levels of MALAT1 lead to the sequestration of nSR100 at the level of nuclear speckles, making clear the mechanism behind the decrease of the dominant negative neuroLSD1 expression levels following stress We found that following a chronic psychosocial stress the expression levels of MALAT1 seem to be positively regulated only in resilient individuals who manage to maintain physiological expression levels of IEG in the hippocampus. Our hypothesis is that only resilient subjects are still able to modulate maladaptive stress-related transcription, thanks to the increased levels of MALAT1, bringing the system back to basal physiological conditions through the negative regulation of neuroLSD1 formation. All this suggests that MALAT1 could be considered a possible hallmark of resilience.