1. A Specific LSD1/KDM1A Isoform Regulates Neuronal Differentiation through H3K9 Demethylation
- Author
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Feizhen Wu, Shichong Liu, Kristina Hempel, Hao Wu, Jernej Murn, Yang Xiang, Lv Ruitu, Ryan Ferrao, Hanno Steen, Benoit Laurent, Yang Shi, and Benjamin A. Garcia
- Subjects
Gene isoform ,animal structures ,Biology ,Methylation ,Medical and Health Sciences ,Histones ,Promoter Regions ,Genetic ,Cell Movement ,Genetics ,Humans ,Protein Isoforms ,education ,Molecular Biology ,Demethylation ,Neurons ,Histone Demethylases ,Regulation of gene expression ,Gene knockdown ,education.field_of_study ,Lysine ,Microfilament Proteins ,Alternative splicing ,Neurosciences ,Membrane Proteins ,Cell Differentiation ,KDM1A ,Cell Biology ,Biological Sciences ,Molecular biology ,Alternative Splicing ,Gene Expression Regulation ,Hela Cells ,Gene Knockdown Techniques ,biology.protein ,Demethylase ,Supervillin ,Developmental Biology - Abstract
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.
- Published
- 2015