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Research ArticleArticle

DNA Methylation and Histone Modification Profiles of Mouse Organic Anion Transporting Polypeptides

Satoki Imai, Ryota Kikuchi, Hiroyuki Kusuhara and Yuichi Sugiyama
Drug Metabolism and Disposition January 2013, 41 (1) 72-78; DOI: https://doi.org/10.1124/dmd.112.047969
Satoki Imai
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (S.I., H.K., R.K.); Phamacokinetics Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan (S.I.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, Riken, Kanagawa, Japan (Y.S.)
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Ryota Kikuchi
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (S.I., H.K., R.K.); Phamacokinetics Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan (S.I.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, Riken, Kanagawa, Japan (Y.S.)
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Hiroyuki Kusuhara
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (S.I., H.K., R.K.); Phamacokinetics Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan (S.I.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, Riken, Kanagawa, Japan (Y.S.)
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Yuichi Sugiyama
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (S.I., H.K., R.K.); Phamacokinetics Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan (S.I.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, Riken, Kanagawa, Japan (Y.S.)
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Abstract

Organic anion transporting polypeptides (rodents, Oatps; human, OATPs) are primarily involved in the transmembrane transportation of a wide range of endogenous and exogenous compounds. Multiple mouse Oatp1 isoforms are closely located on chromosome 6, where each isoform shows distinct tissue distribution; Oatp1b2, Oatp1a6, and Oatp1c1 are expressed exclusively in the liver, kidney, and cerebrum, respectively; Oatp1a1 in the liver and kidney; and Oatp1a4 in the liver and cerebrum. We have identified tissue-dependent differentially methylated region (T-DMR) around the transcriptional start site (TSS) of Oatp1b2, which correlates with its liver-specific expression. Bisulfite sequencing also demonstrated the presence of T-DMRs around the TSS in other Oatp1 genes: CpG dinucleotides at +149 relative to the TSS for Oatp1c1; −48, +101, and +356 for Oatp1a4; −572 and −550 for Oatp1a1; and −122 and +216 for Oatp1a6 were differentially methylated among the liver, kidney, and cerebrum. These methylation profiles were largely consistent with the tissue distribution of Oatp1 mRNAs. Chromatin immunoprecipitation assay revealed that the mRNA expression of Oatp1 genes was accompanied by acetylated histone H3. Human OATP1B1 and OATP1B3 are located on chromosome 12p12 in the OATP1 cluster; both show predominant expression in the liver. These genes also contained T-DMRs that were hypomethylated in the liver, compared with kidney cortex: −511, −411, and +92 relative to the TSS for OATP1B1 and −331, +70, and +73 for OATP1B3. These results suggest that the difference in epigenetic profiles comprising DNA methylation and histone acetylation determines the distinct tissue distribution of Oatp/OATP mRNAs.

Footnotes

  • dx.doi.org/10.1124/dmd.112.047969.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • This study was supported by the Japan Society for the Promotion of Science [Grant-in-Aid for Scientific Research (S) 24229002, Scientific Research (B) 23390034, and Grant-in-Aid for Challenging Exploratory Research 21659037].

  • Received July 21, 2012.
  • Accepted October 2, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (1)
Drug Metabolism and Disposition
Vol. 41, Issue 1
1 Jan 2013
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Research ArticleArticle

Epigenetic Profiles of Mouse Oatps

Satoki Imai, Ryota Kikuchi, Hiroyuki Kusuhara and Yuichi Sugiyama
Drug Metabolism and Disposition January 1, 2013, 41 (1) 72-78; DOI: https://doi.org/10.1124/dmd.112.047969

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Research ArticleArticle

Epigenetic Profiles of Mouse Oatps

Satoki Imai, Ryota Kikuchi, Hiroyuki Kusuhara and Yuichi Sugiyama
Drug Metabolism and Disposition January 1, 2013, 41 (1) 72-78; DOI: https://doi.org/10.1124/dmd.112.047969
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