title: Epigenetic regulation of Atrophin1 by lysine-specific demethylase 1 is required for cortical progenitor maintenance.
abstract: Lysine-specific demethylase 1 (LSD1) is involved in gene regulation and development; however, its precise function, molecular targets and underlying mechanisms during development are poorly understood. Here we show that LSD1 is required for neuronal progenitor cell (NPC) maintenance during cortical development. A ChIP-seq analysis identified a LSD1-binding site (LBAL) downstream of Atrophin1 (ATN1). Surprisingly, tranylcypromine (LSD1 inhibitor) treatment increased H3K4 methylation at LBAL, leading to ATN1 repression and NPC differentiation. Knockdown of LSD1 and ATN1 phenocopied each other in inducing NPC premature differentiation and depletion, which could be rescued by ATN1 overexpression, suggesting that LSD1 controls NPC differentiation via regulation of ATN1 methylation status and expression. The involvement of LSD1 in ATN1 expression and NPC maintenance were confirmed in knockout mice. These findings hint at the potential application for the clinical drug, tranylcypromine, in the prevention and/or treatment of ATN1-associated degenerative disease, dentatorubral-pallidoluysian atrophy.
authors.affiliation: 1] State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Beijing 100101, China [2] University of Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: 1] State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Beijing 100101, China [2] University of Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Xu
authors.affiliation: 1] State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Beijing 100101, China [2] University of Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Beijing 100101, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Sun
authors.affiliation: 1] State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Beijing 100101, China [2] Parkinson's Disease Center, Beijing Institute for Brain Disorders, Beijing 100101, China.
authors.forename: Zhiheng
authors.initials: Z
authors.lastname: Xu
mesh_terms: D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004622:Embryo, Mammalian; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D056466:Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D061251:Primary Cell Culture; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D014191:Tranylcypromine / Q000494:pharmacology
chemical_list: D006657:Histones; D008996:Monoamine Oxidase Inhibitors; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; C095278:atrophin-1; D014191:Tranylcypromine; D056466:Histone Demethylases; C495195:KDM1A protein, human