title: Genome-wide analysis of DNA methylation during antagonism of DMOG to MnCl2-induced cytotoxicity in the mouse substantia nigra.
abstract: Exposure to excessive manganese (Mn) causes manganism, a progressive neurodegenerative disorder similar to idiopathic Parkinson's disease (IPD). The detailed mechanisms of Mn neurotoxicity in nerve cells, especially in dopaminergic neurons are not yet fully understood. Meanwhile, it is unknown whether there exists a potential antagonist or effective drug for treating neuron damage in manganism. In the present study, we report the discovery of an HIF prolyl-hydroxylase inhibitor, DMOG [N-(2-Methoxy-2-oxoacetyl) glycine methyl ester], that can partially inhibit manganese toxicity not only in the neuroblastoma cell line SH-SY5Y in vitro but also in a mouse model in vivo. A genome-wide methylation DNA analysis was performed using microarray hybridization. Intriguingly, DNA methylation in the promoter region of 226 genes was found to be regulated by MnCl2, while the methylation effects of MnCl2 could be restored with combinatorial DMOG treatment. Furthermore, we found that genes with converted promoter methylation during DMOG antagonism were associated across several categories of molecular function, including mitochondria integrity maintain, cell cycle and DNA damage response, and ion transportation. Collectively, our results serve as the basis of a mechanism analysis of neuron damage in manganism and may supply possible gene targets for clinical therapy.
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, People's Republic of China.
authors.forename: Nannan
authors.initials: N
authors.lastname: Yang
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, People's Republic of China.
authors.forename: Tan
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, People's Republic of China.|State Key Laboratory of Medical Genetics, Changsha, 410008 Hunan, People's Republic of China.|Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, 410008 Hunan, People's Republic of China.|Neurodegenerative Disorders Research Centre, Central South University, Changsha, 410008 Hunan, People's Republic of China.
authors.forename: Jifeng
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, People's Republic of China.
authors.forename: Qiying
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, People's Republic of China.
authors.forename: Yacen
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, People's Republic of China.|State Key Laboratory of Medical Genetics, Changsha, 410008 Hunan, People's Republic of China.|Neurodegenerative Disorders Research Centre, Central South University, Changsha, 410008 Hunan, People's Republic of China.
authors.forename: Xinxiang
authors.initials: X
authors.lastname: Yan
authors.affiliation: Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106. USA.
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, People's Republic of China.|State Key Laboratory of Medical Genetics, Changsha, 410008 Hunan, People's Republic of China.|Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, 410008 Hunan, People's Republic of China.|Neurodegenerative Disorders Research Centre, Central South University, Changsha, 410008 Hunan, People's Republic of China.
authors.forename: Beisha
authors.initials: B
authors.lastname: Tang
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, People's Republic of China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D002712:Chlorides / Q000494:pharmacology*; D019175:DNA Methylation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D017895:Manganese Compounds / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009447:Neuroblastoma / Q000188:drug therapy; D009474:Neurons / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D010300:Parkinson Disease / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000600:Amino Acids, Dicarboxylic; D002712:Chlorides; D017895:Manganese Compounds; D014446:Tyrosine 3-Monooxygenase; C025340:manganese chloride; C040947:oxalylglycine