The LSD1/KDM1A neuro-specific isoform regulates neuronal differentiation through H3K9 demethylation [ChIP-Seq]

During brain development, histone-modifying enzymes play an important role by orchestrating transcriptional programs that regulate neuronal maturation. Lysine-Specific Demethylase 1 (LSD1, also named as KDM1A) functions as a transcriptional repressor by removing methyl groups at lysine 4 of histone H3 (H3K4). In neurons, alternative splicing can include an additional exon (exon E8a) within LSD1 transcripts, generating a LSD1+8a neuro-specific isoform. We here report that LSD1+8a isoform does not have the intrinsic ability to demethylate H3K4. LSD1+8a functions as a co-activator on its target genes by removing H3K9 repressive histone marks. We identify the supervillin protein (SVIL) as a LSD1+8a interacting partner and demonstrate that SVIL protein regulates neuronal maturation by controlling LSD1+8a mediated H3K9 demethylation. Thus, our results show that alternative splicing provides a genius mechanism by which LSD1 isoforms can acquire a dual specificity (H3K9 vs H3K4) and therefore differentially control specific gene expression patterns during brain development. Overall design: Examination of 2 different LSD1 isoforms LSD1 and LSD1+8a, LSD1+8a''s cofactor SVIL, H3K9me2 in SH-SY5Y cells infected with control or LSD1+8a shRNA during neuronal maturation induced with BNDF at Day0(B0) and Day3(B3).ChIP-seq datas were generated by deep sequencer Hiseq2500.