title: Analysis of DNA methylation landscape reveals the roles of DNA methylation in the regulation of drug metabolizing enzymes.
abstract: BACKGROUND
  Drug metabolizing enzymes (DMEs) exhibit dramatic inter- and intra-individual variability in expression and activity. However, the mechanisms determining this variability have not been fully elucidated. The aim of this study was to evaluate the biological significance of DNA methylation in the regulation of DME genes by genome-wide integrative analysis.
  
  
  RESULTS
  DNA methylation and mRNA expression profiles of human tissues and hepatoma cells were examined by microarrays. The data were combined with GEO datasets of liver tissues, and integrative analysis was performed on selected DME genes. Detailed DNA methylation statuses at individual CpG sites were evaluated by DNA methylation mapping. From analysis of 20 liver tissues, highly variable DNA methylation was observed in 37 DME genes, 7 of which showed significant inverse correlations between DNA methylation and mRNA expression. In hepatoma cells, treatment with a demethylating agent resulted in upregulation of 5 DME genes, which could be explained by DNA methylation status. Interestingly, some DMEs were suggested to act as tumor-suppressor or housekeeper based on their unique DNA methylation features. Moreover, tissue-specific and age-dependent expression of UDP-glucuronosyltransferase 1A splicing variants was associated with DNA methylation status of individual first exons.
  
  
  CONCLUSIONS
  Some DME genes were regulated by DNA methylation, potentially resulting in inter- and intra-individual differences in drug metabolism. Analysis of DNA methylation landscape facilitated elucidation of the role of DNA methylation in the regulation of DME genes, such as mediator of inter-individual variability, guide for correct alternative splicing, and potential tumor-suppressor or housekeeper.
authors.affiliation: Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwa-Gun 028-3694 Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Habano
authors.affiliation: Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwa-Gun 028-3694 Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Kawamura
authors.affiliation: Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwa-Gun 028-3694 Japan.
authors.forename: Natsuki
authors.initials: N
authors.lastname: Iizuka
authors.affiliation: Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwa-Gun 028-3694 Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Terashima
authors.affiliation: Department of Diagnostic Pathology, School of Medicine, Iwate Medical University, Iwate, Japan.
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Sugai
authors.affiliation: Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwa-Gun 028-3694 Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Ozawa
keywords: Alternative splicing; DNA methylation mapping; Differences in drug metabolism; Integrative analysis