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Vol. 12, No. 23, pp. 3693-3702, December 1, 1998
Howard Hughes Medical Institute and Department of Cell and
Developmental Biology, University of Pennsylvania School of
Medicine, Philadelphia, Pennsylvania 19104 USA
Differentially methylated sequences associated with imprinted genes
are proposed to control genomic imprinting. A 2-kb region located
5' to the imprinted mouse H19 gene is hypermethylated on
the inactive paternal allele throughout development. To determine whether this differentially methylated domain (DMD) is required for
imprinted expression at the endogenous locus, we have generated mice
harboring a 1.6-kb targeted deletion of the DMD and assayed for allelic
expression of H19 and the linked, oppositely imprinted Igf2 gene. H19 is activated and Igf2 expression
is reduced when the DMD deletion is paternally inherited; conversely,
upon maternal transmission of the mutation, H19 expression is
reduced and Igf2 is activated. Consistent with the DMD's
hypothesized role of setting up the methylation imprint, the mutation
also perturbs allele-specific methylation of the remaining H19
sequences. In conclusion, these experiments show that the H19
hypermethylated 5' flanking sequences are required to silence
paternally derived H19. Additionally, these experiments
demonstrate a novel role for the DMD on the maternal chromosome where
it is required for the maximal expression of H19 and the
silencing of Igf2. Thus, the H19 differentially methylated sequences are required for both H19 and Igf2 imprinting.
[Key Words: Differentially methylated domain; DNA methylation; H19; Igf2; genomic imprinting]
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