PT - JOURNAL ARTICLE AU - Imai, Satoki AU - Kikuchi, Ryota AU - Kusuhara, Hiroyuki AU - Sugiyama, Yuichi TI - DNA Methylation and Histone Modification Profiles of Mouse Organic Anion Transporting Polypeptides AID - 10.1124/dmd.112.047969 DP - 2012 Jan 01 TA - Drug Metabolism and Disposition PG - dmd.112.047969 4099 - http://dmd.aspetjournals.org/content/early/2012/10/02/dmd.112.047969.short 4100 - http://dmd.aspetjournals.org/content/early/2012/10/02/dmd.112.047969.full AB - Organic anion transporting polypeptides (rodents, Oatps; human, OATPs) are primarily involved in the transmembrane transport 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.