title: Destabilizing LSD1 by Jade-2 promotes neurogenesis: an antibraking system in neural development.
abstract: Histone H3K4 demethylase LSD1 plays an important role in stem cell biology, especially in the maintenance of the silencing of differentiation genes. However, how the function of LSD1 is regulated and the differentiation genes are derepressed are not understood. Here, we report that elimination of LSD1 promotes embryonic stem cell (ESC) differentiation toward neural lineage. We showed that the destabilization of LSD1 occurs posttranscriptionally via the ubiquitin-proteasome pathway by an E3 ubiquitin ligase, Jade-2. We demonstrated that Jade-2 is a major LSD1 negative regulator during neurogenesis in vitro and in vivo in both mouse developing cerebral cortices and zebra fish embryos. Apparently, Jade-2-mediated degradation of LSD1 acts as an antibraking system and serves as a quick adaptive mechanism for re-establishing epigenetic landscape without more laborious transcriptional regulations. As a potential anticancer strategy, Jade-2-mediated LSD1 degradation could potentially be used in neuroblastoma cells to induce differentiation toward postmitotic neurons.
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Han
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Gui
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Engineering, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Xiong
authors.affiliation: Key Laboratory of Mental Health, Ministry of Health, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Linnan
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liang
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Luyang
authors.initials: L
authors.lastname: Sun
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Yu
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Wenzhe
authors.initials: W
authors.lastname: Si
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Ruorong
authors.initials: R
authors.lastname: Yan
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Yi
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Di
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Wanjin
authors.initials: W
authors.lastname: Li
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Li
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Yang
authors.affiliation: 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Translational Center for Stem Cell Research, Tongji Hospital, Stem Cell Research Center, Tongji University School of Medicine, Shanghai 200065, China; Departments of Psychiatry and Behavioral Sciences and Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Yi Eve
authors.initials: YE
authors.lastname: Sun
authors.affiliation: Key Laboratory of Mental Health, Ministry of Health, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Dai
authors.initials: D
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Engineering, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Anming
authors.initials: A
authors.lastname: Meng
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China; 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin 300070, China. Electronic address: yshang@hsc.pku.edu.cn.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Shang
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D053595:Embryonic Stem Cells / Q000378:metabolism*; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D006367:HeLa Cells; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism* / Q000503:physiopathology; D055495:Neurogenesis; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D029961:Zebrafish Proteins; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; D010089:Oxidoreductases, N-Demethylating; D044767:Ubiquitin-Protein Ligases