title: Tet1-mediated DNA demethylation regulates neuronal cell death induced by oxidative stress.
abstract: Epigenetic regulations including DNA methylation and demethylation play critical roles in neural development. However, whether DNA methylation and demethylation may play a role in neuronal cell death remains largely unclear. Here we report that the blockade of DNA methyltransferase inhibits apoptosis of cerebellar granule cells and cortical neurons in response to oxidative stress. We found that knockdown of ten-eleven translocation methylcytosine dioxygenase (Tet1), a critical enzyme for DNA demethylation, significantly increase apoptosis of cerebellar granule cells induced by hydrogen peroxide. Moreover, cerebellar granule cells from tet1(null) mice appeared to be more sensitive to oxidative stress, suggesting the critical role of Tet1 in neuronal cell death. We further showed that the expression of Klotho, an antiaging protein, in cerebellar granule cells is tightly regulated by DNA methylation. Finally, we found that knockdown of Klotho diminished the rescue effects of DNA methyltransferase inhibitors and Tet1 on neuronal cell death induced by oxidative stress. Our work revealed the role of Tet1-mediated DNA demethylation on neuronal protection against oxidative stress and provided the molecular mechanisms underlying the epigenetic regulation of neuronal cell death, suggesting the role of Klotho in regulating neuronal cell death in response to oxidative stress.
authors.affiliation: 1] Institute of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai. 200031, China [2] University of Chinese Academy of Sciences, Shanghai. 200031, China.
authors.forename: Yong-Juan
authors.initials: YJ
authors.lastname: Xin
authors.affiliation: 1] Institute of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai. 200031, China [2] University of Chinese Academy of Sciences, Shanghai. 200031, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.affiliation: 1] Institute of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai. 200031, China [2] University of Chinese Academy of Sciences, Shanghai. 200031, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yu
authors.affiliation: 1] Institute of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai. 200031, China [2] University of Chinese Academy of Sciences, Shanghai. 200031, China.
authors.forename: Yu-Qing
authors.initials: YQ
authors.lastname: Wang
authors.affiliation: Institute of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai. 200031, China.
authors.forename: Jia-Jia
authors.initials: JJ
authors.lastname: Wu
authors.affiliation: Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China. 201102.
authors.forename: Wen-Hao
authors.initials: WH
authors.lastname: Zhou
authors.affiliation: Institute of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai. 200031, China.
authors.forename: Zilong
authors.initials: Z
authors.lastname: Qiu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002545:Brain Ischemia / Q000209:etiology / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000077209:Decitabine; D005786:Gene Expression Regulation / Q000187:drug effects; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C540839:TET1 protein, mouse; D000077209:Decitabine; D006861:Hydrogen Peroxide; D005966:Glucuronidase; D000090265:Klotho Proteins; D001374:Azacitidine