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Developmental Changes in DNA Methylation of CYP3A5 in Human Liver
Author(s) -
Vyhlidal Carrie,
Bi Charlie,
Gaedigk Roger,
Ye Shui,
Kingsmore Stephen,
Leeder J.
Publication year - 2015
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.29.1_supplement.619.2
Subject(s) - methylation , dna methylation , cpg site , biology , bisulfite sequencing , microbiology and biotechnology , gene , promoter , genotype , genetics , gene expression
CYP3A5 is polymorphically expressed in human prenatal and postnatal liver due to the presence or absence of the CYP3A5*3 allelic variant. However, expression of members of the CYP3A subfamily recently has been reported to be regulated through DNA methylation. The object of this study was to examine changes in CpG methylation of the CYP3A5 gene in human pediatric and prenatal liver. Methylation status of CpG dinucleotides was initially determined in 16 pediatric livers using Agilent SureSelect Human Methyl‐Seq and data stratified by age into four groups (20‐96 days; 2‐2.6 yrs; 7‐8 yrs; and 15‐17 yrs). Bisulfite sequencing was performed on 48 pediatric and 34 prenatal livers to confirm results of Methyl‐Seq analysis. Cytosines in the promoter and introns 1 and 7 of CYP3A5 exhibited statistically significant changes in methylation with respect to age group in pediatric livers (p‐values=0.02, 0.03 and 0.02, respectively). Bisulfite sequencing of the CYP3A5 promoter revealed hypermethylation of cytosines at ‐411 and ‐460 in prenatal versus pediatric liver (60% vs 38% and 80% vs 57%, respectively, p<0.0001) which exhibited age‐dependent demethylation during the first year of life (r 2 =0.85, p<0.0001 and r 2 =0.53, p=0.005, respectively). Methylation of cytosines at ‐411 and ‐460 was associated with total CYP3A5 mRNA expression (p<0.0001). Current studies are investigating interactions between genotype and methylation to influence CYP3A5 gene expression.