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Evidence for epigenetic regulation of UGT1A1 protein expression and activity in healthy human livers
Author(s) -
Yasar Umit,
Greenblatt David J,
Guillemette Chantal,
Court Michael H.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.270.5
Subject(s) - cpg site , glucuronidation , methylation , epigenetics , dna methylation , biology , enhancer , microbiology and biotechnology , endocrinology , genetics , transcription factor , gene expression , gene , in vitro , microsome
Interindividual variability in UDP‐glucuronosyltransferase 1A1 (UGT1A1) is only partially explained by genetic polymorphisms and enzyme inducers. Here we determined whether cytosine methylation explains an additional proportion of this variability in human liver. UGT1A1 phenotypes, including UGT1A1 protein and bilirubin glucuronidation, and UGT1A1*28 were determined using a human liver bank (n=46). Methylation levels were quantified at 5 CpG sites associated with known transcription factor response elements in the UGT1A1 promoter and distal enhancer, as well as a CpG‐rich island 1.5 kb further upstream. Individual CpG sites showed considerable methylation variability ranging from 10‐ to 29‐fold difference with average methylation levels from 25 to 41%. Multivariate regression analysis identified *28/*28 genotype, −4 CpG site methylation, and alcohol history as significant predictors of UGT1A1 protein content, accounting for 12%, 11%, and 9% of the variability (R2=0.32, p=0.003). Similarly, −4 CpG methylation and alcohol history accounted for 13% and 12% of the variability in bilirubin glucuronidation (R2=0.25, p=0.005). These results suggest that differential methylation of the −4 CpG site located within a known USF response element may explain a proportion of variability in hepatic glucuronidation by UGT1A1. Funded by NIH‐R01‐ GM061834 (to MHC) and NIH‐N01‐DK‐7–0004/ HHSN267200700004C.