Alternative splicing as possible contributor to LSD1 epigenetic tuneability in the mammalian nervous system

Chromatin represents the substrate of epigenetic regulation underlying several biological processes, including DNA replication, transcription, lineage commitment and cell response to environmental stimuli. Recent advances suggest chromatin involvement in the mammalian nervous system and its active remodelling consequent to synaptic activity, finally leading to the acquisition and dynamic maintenance of neuronal phenotype. Mechanisms such as DNA methylation, ATP-dependent remodelling and posttranslational modifications on basic N-terminal histone tails all contribute to the histone code, altering chromatin accessibility to transcriptional machinery. In this context acts the enzyme LSD1 - Lysine Specific Demethylase 1 - whose epigenetic activity relies on specific demethylation of mono and dimethylated H3K4 residues, through an amino oxidase reaction, resulting in repression of target genes, which is achieved through concomitant recruitment of LSD1 and its associated factors, such as members of the CoREST-corepressor complex. Although several efforts have been focused on LSD1 enzymatic activity and its cognate effectors, neither its function not its own regulation have been fully elucidated. According to experimental data, LSD1 transcript can encompass several splice isoforms, some of which display a remarkable neuro-specific pattern of expression, while apparently retaining comparable activities. The arousal of such splice isoforms in the earliest murine embrional stages and their progression over subsequent stages of SNC development account for LSD1 role in neural commitment. Moreover, maintenance of LSD1 splice variants in post-mitotic, terminally differentiated neurons, before and after depolarizing stimuli suggests that alternative splicing could possibly contribute to LSD1 epigenetic tuneability in the nervous system.