Allele-specific expression and gene methylation in the control of CYP1A2 mRNA level in human livers.
The basis for interindividual variation in the CYP1A2 gene expression is not fully understood and the known genetic polymorphisms in the gene provide no explanation. We investigated whether the CYP1A2 gene expression is regulated by DNA methylation and displays allele-specific expression (ASE) using 65 human livers. Forty-eight percent of the livers displayed ASE not associated to the CYP1A2 mRNA levels. The extent of DNA methylation of a CpG island including 17 CpG sites, close to the translation start site, inversely correlated with hepatic CYP1A2 mRNA levels (P=0.018). The methylation of two separate core CpG sites was strongly associated with the CYP1A2 mRNA levels (P=0.005) and ASE phenotype (P=0.01), respectively. The CYP1A2 expression in hepatoma B16A2 cells was strongly induced by treatment with 5-aza-2'-deoxycytidine. In conclusion, the CYP1A2 gene expression is influenced by the extent of DNA methylation and displays ASE, mechanisms contributing to the large interindividual differences in CYP1A2 gene expression.
Ghotbi
Roza
R
Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
Gomez
Alvin
A
Milani
Lili
L
Tybring
Gunnel
G
Syvänen
Ann-Christine
AC
Bertilsson
Leif
L
Ingelman-Sundberg
Magnus
M
Aklillu
Eleni
E
D000483:Alleles; D001483:Base Sequence; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D004247:DNA; D019175:DNA Methylation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008969:Molecular Sequence Data; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D004247:DNA; D019388:Cytochrome P-450 CYP1A2