LSD1 and the lncRNA MALAT1: a mammalian epigenetic pathway involved in environmental adaptation

Many Long Non Coding RNAs (lncRNAs) are implicated in nervous system development and neuronal activity modulation, making them important physiological actors but also potential vulnerability hotspots for neuropsychiatric diseases. Among them, the lncRNA MALAT1 plays a role in synaptic and electric activity modulation: in line its dysregulation is linked with diseases characterized by an altered neuronal excitability, such as epilepsy and schizophrenia. MALAT1 is involved in the control of splicing events as being able to sequester some SR-family splicing factors in nuclear inactive compartments, hampering their activity on target transcripts. nSR100, that belongs to the SR-family, is the main splicing regulator promoting the generation of neuroLSD1 by the inclusion of an alternative exon (E8a) in Lysine Specific Demethylase 1 (LSD1) mature transcripts. We hypothesized that MALAT1 may be a novel actor in the modulation of exon E8a inclusion in LSD1 transcripts, by sequestering nSR100, ultimately modulating the ratio between LSD1 and neuroLSD1. Indeed, the LSD1/neuroLSD1 balance, setting the expression of plasticity genes in response to environmental stimuli, can be transiently modified by neuronal activation and psychosocial stress, ultimately restraining glutamatergic synaptic excitability. In support of our hypothesis, MALAT1 up- or down-regulation respectively induce a decrease or increase in E8a inclusion in mature transcripts. As well, MALAT1 reduced activity promotes neuroLSD1 expression and prevents its downregulation upon depolarization. Moreover, both in in-vitro and in-vivo neuronal activation, the transient downregulation of neuroLSD1 is anticipated by a rapid transactivation of MALAT1. The ability of this lncRNA to concur in the modulation of LSD1/neuroLSD1 ratio would unveil a novel pathway involved in neuronal homeostasis control and, potentially, also a new mechanism implicated in disorders characterized by altered neuronal excitability control.