title: Genetic and epigenetic regulation on the transcription of GABRB2: Genotype-dependent hydroxymethylation and methylation alterations in schizophrenia.
abstract: To improve our understanding of the abnormalities and non-Mendelian inheritance characteristics of schizophrenia, this study examined DNA methylation (5mC) and hydroxymethylation (5hmC) in the schizophrenia-associated GABRB2 gene encoding the type A γ-aminobutyric acid receptor β2subunit. DNAs from the peripheral white blood cells of 279 schizophrenic patients and 256 controls from the Chinese Han population were examined to reveal that the GABRB2 promoter P1-5mC level which was correlated with olanzapine administration, P2-5mC/5hmC level, and Alu-5mC level which was correlated with administration of ziprasidone or oxcarbazepine, were increased in schizophrenic patients. Significant correlations of the promoter 5mC/5hmC levels with the genotypes of single nucleotide polymorphisms (SNPs) were observed with SNPs rs72815526 (C/A) and rs3811997 (C/T). In schizophrenics, the heterozygous genotypes of rs72815526 (C/A) were correlated with increased 5hmC levels whereas the heterozygous genotypes of rs3811997 (C/T) were correlated with decreased 5mC levels. Moreover, the GABRB2 promoter with rs3811997(C/T) minor allele T or the methylation-disrupted type AG at -254 and -231 CCGG sites was observed to enhance the promoter activity in the luciferase reporter-transfected human embryonic kidney 293 cells. An elevated GABRB2 mRNA transcriptional level in human neuroblastoma IMR32 cells were accompanied by the decreased promoter 5hmC/5mC levels induced by 5-azacytidine or by increased histone H4 acetylation levels of the Alu-Yi6 region induced by valproic acid. These results reveal alterations in GABRB2 genotype-dependent methylation and hydroxymethylation in schizophrenia, which yielded transcriptional and translational alterations in the cultured cells, and help elucidate the genetic-epigenetic interactions influencing schizophrenia.
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, Guangdong, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zong
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, Guangdong, China; Key Laboratory of Genetics and Birth Health of Hunan Province, Family Planning Institute of Hunan Province, Changsha, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, Guangdong, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Department of Psychiatry, Guangzhou First People's Hospital, Guangzhou, Guangdong, China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, Guangdong, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: The Third People's Hospital of Zhongshan, Zhongshan, Guangdong, China.
authors.forename: Wenwei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, Guangdong, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, Shenzhen Kangning Hospital & Shenzhen Mental Health Center, Shenzhen, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, Guangdong, China.
authors.forename: Shiqing
authors.initials: S
authors.lastname: Wang
authors.affiliation: The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Deng
authors.affiliation: The Third People's Hospital of Zhongshan, Zhongshan, Guangdong, China.
authors.forename: Zhizhen
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, Guangdong, China.
authors.forename: Shufen
authors.initials: S
authors.lastname: Li
authors.affiliation: The Third People's Hospital of Zhongshan, Zhongshan, Guangdong, China.
authors.forename: Jiming
authors.initials: J
authors.lastname: Hu
authors.affiliation: Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, Guangdong, China. Electronic address: cyzhao@smu.edu.cn.
authors.forename: Cunyou
authors.initials: C
authors.lastname: Zhao
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use; D044466:Asian People / Q000208:ethnology / Q000235:genetics; D001569:Benzodiazepines / Q000627:therapeutic use; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011963:Receptors, GABA-A / Q000235:genetics* / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D014150:Antipsychotic Agents; C495710:GABRB2 protein, human; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D000077152:Olanzapine
keywords: 5-azacytidine; 5hmC/5mC; Hypermethylation; RNA expression; SNP; Valproic acid