Analysis of DNA methylation and histone modification profiles of liver-specific transporters.
Tissue-specific expression of transporters is tightly linked with their physiological functions through the regulation of the membrane transport of their substrates. We hypothesized that epigenetic regulation underlies the tissue-specific expression of mouse liver-specific transporters (Oatp1b2/Slco1b2, Ntcp/Slc10a1, Bsep/Abcb11, and Abcg5/g8). We examined their DNA methylation and histone modification profiles near the transcriptional start site (TSS) in the liver, kidney, and cerebrum. Genome-wide DNA methylation profiling with tissue-dependent differentially methylated region profiling with restriction tag-mediated amplification and subsequent bisulfite genomic sequencing demonstrated that the CpG dinucleotides around the TSS of Oatp1b2 (from -515 to +149 CpGs), Ntcp (from -481 to +495 CpGs), Bsep (from -339 to +282 CpGs), and Abcg5/g8 (from -161 to +5 CpGs for Abcg5, i.e., from -213 to -48 CpGs for Abcg8) were hypomethylated in the liver and hypermethylated in the kidney and cerebrum. The opposite pattern was observed for Pept2/Slc15a2 (from -638 to +4 CpGs), which was expressed in the kidney and cerebrum but not in the liver. These DNA methylation profiles are consistent with the tissue distribution of these transporters. A chromatin immunoprecipitation assay demonstrated that the histone H3 associated with Oatp1b2, Ntcp, Bsep, and Abcg5/g8 promoters was hyperacetylated in the liver but was acetylated very little in the kidney and cerebrum, whereas the upstream region of Pept2 was hyperacetylated only in the kidney and cerebrum. These results suggest the involvement of epigenetic systems in the tissue-specific expression of mouse transporters Oatp1b2, Ntcp, Bsep, Abcg5/g8, and Pept2.
Imai
Satoki
S
Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Kikuchi
Ryota
R
Kusuhara
Hiroyuki
H
Yagi
Shintaro
S
Shiota
Kunio
K
Sugiyama
Yuichi
Y
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000107:Acetylation; D000818:Animals; D054022:Cerebrum / Q000378:metabolism; D019175:DNA Methylation / Q000502:physiology*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity / Q000235:genetics; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D027981:Symporters / Q000235:genetics / Q000378:metabolism*
C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; C490549:Abcb11 protein, mouse; D006657:Histones; D008074:Lipoproteins; D027381:Liver-Specific Organic Anion Transporter 1; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent; C498887:Slco1b2 protein, mouse; D027981:Symporters; C071908:sodium-bile acid cotransporter