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Mol Cell. 2015 Mar 19;57(6):957-970. doi: 10.1016/j.molcel.2015.01.010. Epub 2015 Feb 12.

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

Author information

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: yang_shi@hms.harvard.edu.

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.

PMID:
25684206
PMCID:
PMC4369399
DOI:
10.1016/j.molcel.2015.01.010
[Indexed for MEDLINE]
Free PMC Article

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