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Analysis of DNA methylation landscape reveals the roles of DNA methylation in the regulation of drug metabolizing enzymes.

Habano W, Kawamura K, Iizuka N, Terashima J, Sugai T, Ozawa S - Clin Epigenetics (2015)

Bottom Line: Moreover, tissue-specific and age-dependent expression of UDP-glucuronosyltransferase 1A splicing variants was associated with DNA methylation status of individual first exons.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwa-Gun 028-3694 Japan.

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.

No MeSH data available.


Related in: MedlinePlus

Classification of DME genes based on the corresponding DNA methylation landscape
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Fig7: Classification of DME genes based on the corresponding DNA methylation landscape

Mentions: Interestingly, DME genes had unique features of the DNA methylation landscape (Fig. 1), which could be classified into at least three groups, as summarized in Fig. 7. The first group showed highly variable methylation among normal livers (maximum βR > 0.296) and inverse correlations with mRNA expression. DME genes in this first group may be candidates for explaining inter-individual variations in drug metabolizing activity; we classified genes in this group as the highly variable methylation (HVM) type. Genes in the second group, similar to the CYP1B1 gene, showed stable methylation statuses among normal livers but were hypermethylated in tumor cells. These DNA methylation features were similar to those of tumor suppressor genes (i.e., the TSG type). The last group retained low levels of methylation in both normal and tumor livers, suggesting these genes may act as housekeeping genes. Typical housekeeping genes, such as ACTB and GAPDH, had similar features of methylation mapping and expression profiles in our study. For example, the level of DNA methylation was highly stable and low in the 5′ regulatory region (hypomethylated 5′UTR) but considerably high within the gene body (hypermethylated exons). In addition, the mRNA expression of the housekeeping genes was stable among normal livers, with CVs of less than 17.1 %. Although it was difficult to fulfill all these criteria, we found two DME genes (CYP2R1 and CYP46A1) that had characteristics similar to those of housekeeping genes (i.e., HKG type).Fig. 7


Analysis of DNA methylation landscape reveals the roles of DNA methylation in the regulation of drug metabolizing enzymes.

Habano W, Kawamura K, Iizuka N, Terashima J, Sugai T, Ozawa S - Clin Epigenetics (2015)

Classification of DME genes based on the corresponding DNA methylation landscape
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4587720&req=5

Fig7: Classification of DME genes based on the corresponding DNA methylation landscape
Mentions: Interestingly, DME genes had unique features of the DNA methylation landscape (Fig. 1), which could be classified into at least three groups, as summarized in Fig. 7. The first group showed highly variable methylation among normal livers (maximum βR > 0.296) and inverse correlations with mRNA expression. DME genes in this first group may be candidates for explaining inter-individual variations in drug metabolizing activity; we classified genes in this group as the highly variable methylation (HVM) type. Genes in the second group, similar to the CYP1B1 gene, showed stable methylation statuses among normal livers but were hypermethylated in tumor cells. These DNA methylation features were similar to those of tumor suppressor genes (i.e., the TSG type). The last group retained low levels of methylation in both normal and tumor livers, suggesting these genes may act as housekeeping genes. Typical housekeeping genes, such as ACTB and GAPDH, had similar features of methylation mapping and expression profiles in our study. For example, the level of DNA methylation was highly stable and low in the 5′ regulatory region (hypomethylated 5′UTR) but considerably high within the gene body (hypermethylated exons). In addition, the mRNA expression of the housekeeping genes was stable among normal livers, with CVs of less than 17.1 %. Although it was difficult to fulfill all these criteria, we found two DME genes (CYP2R1 and CYP46A1) that had characteristics similar to those of housekeeping genes (i.e., HKG type).Fig. 7

Bottom Line: Moreover, tissue-specific and age-dependent expression of UDP-glucuronosyltransferase 1A splicing variants was associated with DNA methylation status of individual first exons.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwa-Gun 028-3694 Japan.

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.

No MeSH data available.


Related in: MedlinePlus