Extensive tissue-specific variation of allelic methylation in the Igf2 gene during mouse fetal development: relation to expression and imprinting

The imprinted Igf2 gene is active only on the paternal allele in most tissu es. Its imprinting involves a cis-acting imprinting-control region (ICR) lo cated upstream of the neighboring and maternally expressed H19 gene, It is thought that differential methylation of the parental alleles at the ICR is crucial for parental imprinting of both genes. Differentially methylated r egions (DMRs) have also been identified within the Igf2 gene and their diff erential methylation is thought to be established during early development. To gain further insight into the function of these DMRs, we performed a qu antitative analysis of their allelic methylation levels in different tissue s during fetal development and the postnatal period in the mouse. Surprisin gly, we found that the methylation levels of Igf2 DMRs vary extensively dur ing fetal development, mostly on the expressed paternal allele. In particul ar, in skeletal muscle, differential allelic methylation in both DMR 1 and DMR 2 occurs only after birth, whereas correct paternal monoallelic express ion is always observed. including in the embryonic stages. This suggests th at differential methylation in the DMR I and DMR 2 of the lgf2 gene is disp ensable for its imprinting in skeletal muscle. Furthermore. progressive met hylation of the Igf2 paternal allele appears to be correlated with concomit ant postnatal down-regulation and silencing of the gene. We discuss possibl e relations between Igf2 allelic methylation and expression during fetal de velopment. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.