DNA methylation and histone modification profiles of mouse organic anion transporting polypeptides.
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.
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Bisulfite Organic anion transporting polypeptides Oatp1 Oatp1 histone H3 Human OATP1B1 OATP1B3 OATP1 T-DMRs TSS OATP1B1 OATP1B3 histone Oatp OATP mouse Oatp1 Oatp1b2 Oatp1a6 Oatp1c1 Oatp1a1 Oatp1a4 tissue-dependent differentially methylated region Oatps T-DMR transcriptional start site TSS Oatp1b2 OATPs T-DMRs TSS Oatp1 TSS Oatp1c1 Oatp1a4 Oatp1a1 Oatp1a6 histone mouse organic anion transporting polypeptides