title: A specific LSD1/KDM1A isoform regulates neuronal differentiation through H3K9 demethylation.
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.
authors: Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston MA, 02115, USA; Department of Cell Biology, Harvard Medical School, Boston MA, 02115, USA.
authors: Benoit
authors: B
authors: Laurent
authors: Department of Biochemistry and Epigenetics Laboratory, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors: Lv
authors: L
authors: Ruitu
authors: Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston MA, 02115, USA; Department of Cell Biology, Harvard Medical School, Boston MA, 02115, USA.
authors: Jernej
authors: J
authors: Murn
authors: Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Proteomics Center, Boston Children's Hospital, Boston, MA 02115, USA.
authors: Kristina
authors: K
authors: Hempel
authors: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
authors: Ryan
authors: R
authors: Ferrao
authors: Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston MA, 02115, USA; Department of Cell Biology, Harvard Medical School, Boston MA, 02115, USA.
authors: Yang
authors: Y
authors: Xiang
authors: Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Shichong
authors: S
authors: Liu
authors: Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Benjamin A
authors: BA
authors: Garcia
authors: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
authors: Hao
authors: H
authors: Wu
authors: Department of Biochemistry and Epigenetics Laboratory, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors: Feizhen
authors: F
authors: Wu
authors: Proteomics Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors: Hanno
authors: H
authors: Steen
authors: Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston MA, 02115, USA; Department of Cell Biology, Harvard Medical School, Boston MA, 02115, USA. Electronic address: yang_shi@hms.harvard.edu.
authors: Yang
authors: Y
authors: Shi
mesh_terms: D017398:Alternative Splicing; D002454:Cell Differentiation; D002465:Cell Movement; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000378:metabolism
chemical_list: D006657:Histones; D008565:Membrane Proteins; D008840:Microfilament Proteins; D020033:Protein Isoforms; C109413:SVIL protein, human; D056466:Histone Demethylases; C495195:KDM1A protein, human; D008239:Lysine