Role for DNA methylation in genomic imprinting

Abstract

THE paternal and maternal genomes are not equivalent and both are required for mammalian development^1,2. The difference between the parental genomes is believed to be due to gamete-specific differential modification, a process known as genomic imprinting. The study of transgene methylation has shown that methylation patterns can be inherited in a parent-of-origin-specific manner^3–7, suggesting that DNA methylation may play a role in genomic imprinting. The functional significance of DNA methylation in genomic imprinting was strengthened by the recent finding that CpG islands (or sites) in three imprinted genes, H19, insulin-like growth factor 2 (Igf-2), and lgf-2 receptor (Igf-2r), are differentially methylated depending on their parental origin^8–12. We have examined the expression of these three imprinted genes in mutant mice that are deficient in DNA methyltransferase activity¹³. We report here that expression of all three genes was affected in mutant embryos: the normally silent paternal allele of the HI9 gene was activated, whereas the normally active paternal allele of the Igf-2 gene and the active maternal allele of theIgf-2r gene were repressed. Our results demonstrate that a normal level of DNA methylation is required for controlling differential expression of the paternal and maternal alleles of imprinted genes.