POST-TRANSCRIPTIONAL AND POST-TRANSLATIONAL REGULATION OF LSD1 IN MAMMALIAN BRAIN

Epigenetic mechanisms play important roles in brain development, orchestrating proliferation, differentiation, and morphogenesis. Lysine-Specific Demethylase 1 (LSD1 also known as KDM1A and AOF2) is a histone modifier involved in transcriptional repression, forming a stable core complex with the corepressors corepressor of REST (CoREST) and histone deacetylases (HDAC1/2). Importantly, in the mammalian CNS, neuronal neuroLSD1, an alternative splicing isoform of LSD1 including the microexon E8a, sets alongside LSD1 and is capable of enhancing neurite growth and morphogenesis. Here, we describe that the morphogenic properties of neuronal neuroLSD1 require switching off repressive activity and this negative modulation is mediated in vivo by phosphorylation of the Thr369b residue coded by exon E8a. Three-dimensional crystal structure analysis using a phospho-mimetic mutant (Thr369bAsp), indicate that phosphorylation affects the residues surrounding the exon E8a-coded amino acids, causing a local conformational change. We suggest that phosphorylation, without affecting demethylase activity, causes in neurons CoREST and HDAC1/2 corepressors detachment from LSD1-8a and impairs neuroLSD1 repressive activity. In neurons, Thr369b phosphorylation is required for morphogenic activity, converting neuronal LSD1-8a in a dominant-negative isoform, challenging LSD1-mediated transcriptional repression on target genes. We show that in the hippocampus LSD1 together with HDAC2 are co-repressors of SRF and involved in the transcriptional regulation of egr1 and c-fos. Consistent with neuroLSD1 dominant negative function, neuroLSD1KO mice display a more repressed epigenetic landscape in terms of reduced histone H3K4 methylation and H3 acetylation levels at egr1 and c-fos promoters.