A specific LSD1/KDM1A isoform regulates neuronal differentiation through H3K9 demethylation

Mol Cell. 2015 Mar 19;57(6):957-970. doi: 10.1016/j.molcel.2015.01.010.

Benoit Laurent ¹, Lv Ruitu ², Jernej Murn ¹, Kristina Hempel ³, Ryan Ferrao ⁴, Yang Xiang ¹, Shichong Liu ⁵, Benjamin A Garcia ⁵, Hao Wu ⁴, Feizhen Wu ², Hanno Steen ⁶, Yang Shi ⁷

Affiliations

1 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.
2 Department of Biochemistry and Epigenetics Laboratory, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.
3 Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Proteomics Center, Boston Children's Hospital, Boston, MA 02115, USA.
4 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.
5 Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
6 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.
7 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: [email protected].

PMID: 25684206 DOI: 10.1016/j.molcel.2015.01.010

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.

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