Specific Cytosine Demethylations within the First Exons of the Rat CYP2D3 and CYP2D5 Genes Are Associated with Activation of Hepatic Gene Expression during Development

Abstract

To investigate the mechanism of transcriptional activation of the CYP2D gene subfamily in rat liver during development, Northern blot analysis and DNA methylation tests using Hpa II and Hha I enzymes, which are sensitive to cytosine methylated DNA, were carried out. As the result of mRNA measurements, these genes were classified into two patterns of expression, (i) late-onset gene activation in which mRNA gradually increases until rats reach puberty and (ii) early-onset expression in which the peak of mRNA expression is reached within 1 week after birth. The CYP2D3 and CYP2D5 genes, representatives of late-onset and early-onset expression, respectively, were examined. A correlation was found between mRNA expression during development and demethylation of cytosine residues located at the same position in the first exons of both the CYP2D3 and CYP2D5 genes. These results suggest that specific demethylation events are associated with developmentally programmed hepatic gene activation.