title: Coordinated regulation of dendrite arborization by epigenetic factors CDYL and EZH2.
abstract: Dendritic arborization is one of the key determinants of precise circuits for information processing in neurons. Unraveling the molecular mechanisms underlying dendrite morphogenesis is critical to understanding the establishment of neuronal connections. Here, using gain- and loss-of-function approaches, we defined the chromodomain protein and transcription corepressor chromodomain Y-like (CDYL) protein as a negative regulator of dendrite morphogenesis in rat/mouse hippocampal neurons both in vitro and in vivo. Overexpressing CDYL decreased, whereas knocking it down increased, the dendritic complexity of the primary cultured rat neurons. High-throughput DNA microarray screening identified a number of CDYL downstream target genes, including the brain-derived neurotrophic factor (BDNF). Knock-down of CDYL in neuronal cells led to increased expression of BDNF, which is primarily responsible for CDYL's effects on dendrite patterns. Mechanistically, CDYL interacts with EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), directly and recruits the H3K27 methyltransferase activity to the promoter region of the BDNF gene. In doing so, CDYL and EZH2 coordinately restrict dendrite morphogenesis in an interdependent manner. Finally, we found that neural activity increased dendritic complexity through degradation of CDYL protein to unleash its inhibition on BDNF. These results link, for the first time, the epigenetic regulators CDYL and EZH2 to dendrite morphogenesis and might shed new light on our understanding of the regulation of the neurodevelopment.
authors.affiliation: Neuroscience Research Institute, Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission and Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China, and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China.
authors.forename: Cai
authors.initials: C
authors.lastname: Qi
authors.forename: Shumeng
authors.initials: S
authors.lastname: Liu
authors.forename: Rui
authors.initials: R
authors.lastname: Qin
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Wang
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Shang
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Liang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D056970:Co-Repressor Proteins; D003712:Dendrites / Q000502:physiology*; D004622:Embryo, Mammalian; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D006836:Hydro-Lyases; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013997:Time Factors
chemical_list: D056970:Co-Repressor Proteins; D011506:Proteins; D034741:RNA, Small Interfering; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C118458:CDYL protein, human; D006836:Hydro-Lyases