Disruption of epigenetic control at Igf2/H19 loci in thymus of p53-deficient mice

Abstract

Differential DNA methylation depending on the parental origin is a typical epigenetic modification in genomic imprinting. Igf2 is a maternally imprinted gene linked to the paternally imprinted H19 on mouse chromosome 7, being expressed exclusively from the hypermethylated paternal allele of Igf2. Differential DNA methylation pattern on ICR (imprinting control region) located on 2kb upstream of H19 is allelically most distinctive among DMRs (differentially methylated region), i.e., DMR1 on Igf2 promoter and DMR2 on exon 4 - 6 of Igf2. An increased expression of human IGF2 and hypermethylation on the maternal allele of ICR cause Wilms’ tumor and colorectal cancers. In this study, we attempted to detect the early epigenetic changes in p53-deficient mice. The methylation status of ICR at Igf2/H19 loci was determined in p53 +/- and p53 -/- mice. Differential DNA methylation pattern of ICR on Igf2/H19 loci was disrupted in thymus of p53 +/- and p53 -/- mice. The 5’-ICR and 3’-ICR were hypomethylated and hypermethylated, respectively. “All-or-none” pattern of the DNA methylation in region A was corrupted with a tendency of hypomethylation upon decreasing dosages of p53. On the contrary, the DNA methylation pattern in region B was less corrupted than that in region A. Region B was rather methylated simultaneously in cis. The imprinted expression pattern of Igf2 and H19 were also disrupted in thymus of p53 +/- and p53 -/- mice. Igf2 expression was dramatically reduced in thymus of p53 +/- and p53 -/- mice. The repression of Igf2 well-correlates with hypomethylation of region A in thymus. The mRNA level of H19, a reciprocally imprinted gene, was also decreased in thymus of p53 -/- mice. Dnmt3L was dramatically repressed in the thymus of p53 +/- and p53 -/- mice, while the expression patterns of Dnmt1, Dnmt3a, and Dnmt3b in p53-deficient mice remained constant in the tissues tested. Impaired imprinting of Igf2/H19 and deregulated expression of DNA methylation machinery pr...