Imprinting, the differential expression of the two alleles of a gene based on their parental origin, requires that the alleles be distinguished or marked. A candidate for the differentiating mark is DNA methylation. The maternally expressed H19 gene is hypermethylated on the inactive paternal allele in somatic tissues and sperm, but to serve as the mark that designates the imprint, differential methylation must also be present in the gametes and the pre–implantation embryo. We now show that the pattern of differential methylation in the 5′ portion of H19 is established in the gametes and a subset is maintained in the pre–implanation embryo. That subset is sufficient to confer monoallelic expression to the gene in blastocysts. We propose that paternal–specific methylation of the far 5′ region is the mark that distinguishes the two alleles of H19.
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