Post-transcriptional and post-translational regulation of LSD1 epigenetic activity modulates morphogenesis in neurons

The flexible nature of neurons is regulated by a complex molecular machinery coupling gene expression to neuronal activation and epigenetic mechanisms are now emerging as key regulators of such process. Neuronal LSD1-8a (Lysine Specific Demethylase 1 including exon E8a) is a mammal restricted neurospecific isoform of the histone demethylase LSD1 generated by alternative splicing. Neuronal LSD1-8a displays demethylase activity on mono- and di-methylated H3-Lys4 and unique pro-maturation properties in cortical neurons. Structural analysis of the protein showed that in neuronal LSD1-8a, the amino acids coded by exon E8a form a loop protruding from the amino oxidase domain in close proximity to the substrate entry site. We discovered that in the brain, this loop contains a threonine phosphorylation site required for the pro-maturation effect. Indeed, in cortical neurons exon E8a phosphorylation is pivotal to induce neurite outgrowth, ampering the transcriptional repressive activity of neuronal LSD1-8a. Post-translational modification of LSD1 represents therefore a dynamic regulatory mechanism in response to neuronal activity. During development we observed that the amount of neuronal LSD1-8a is post-transcriptionally definened by alternative splicing in a highly dynamic fashion. In adult mice a steady level is reached and maintained constant in resting conditions. We present in vivo evidence that pharmacologically induced neuronal activation, is able to affect the ratio of LSD1/LSD1-8a, and that brain specific splicing factors regulate this process. Our data suggest that levels of the pro-maturation phospho-LSD1-8a isoform are dually regulated in response to neuronal stimuli