A Specific LSD1/KDM1A Isoform Regulates Neuronal Differentiation through H3K9 Demethylation

Benoit Laurent, Lv Ruitu, Jernej Murn, Kristina Hempel, Ryan Ferrao, Yang Xiang, Shichong Liu, Benjamin A. Garcia, Hao Wu, Feizhen Wu, Hanno Steen, Yang Shi

Research output: Contribution to journalArticlepeer-review

186 Scopus citations


Lysine-specific demethylase 1 (LSD1) has been reported to repress and activate transcription by mediating histone H3K4me1/2 and H3K9me1/2 demethylation, respectively. The molecular mechanism that underlies this dual substrate specificity has remained unknown. Here we report that an isoform of LSD1, LSD1+8a, does not have the intrinsic capability to demethylate H3K4me2. Instead, LSD1+8a mediates H3K9me2 demethylation in collaboration with supervillin (SVIL), a new LSD1+8a interacting protein. LSD1+8a knockdown increases H3K9me2, but not H3K4me2, levels at its target promoters and compromises neuronal differentiation. Importantly, SVIL co-localizes to LSD1+8a-bound promoters, and its knockdown mimics the impact of LSD1+8a loss, supporting SVIL as a cofactor for LSD1+8a in neuronal cells. These findings provide insight into mechanisms by which LSD1 mediates H3K9me demethylation and highlight alternative splicing as a means by which LSD1 acquires selective substrate specificities (H3K9 versus H3K4) to differentially control specific gene expression programs in neurons.

Original languageEnglish
Pages (from-to)957-970
Number of pages14
JournalMolecular cell
Issue number6
StatePublished - Mar 19 2015


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