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Vol. 14, No. 10, pp. 1186-1195, May 15, 2000
Laboratory of Mammalian Genes and Development, National Institute of
Child Health and Human Development, Bethesda, Maryland 20892 USA
H19 and Igf2 are expressed in a monoallelic fashion
from the maternal and paternal chromosomes, respectively. A region
upstream of H19 has been shown to regulate such imprinted
expression of both genes in cis. We have taken advantage of a
loxP/cre recombinase-based strategy to delete
this region in mice in a conditional manner to determine the temporal
requirement of the upstream region in initiating and maintaining the
imprinted expression of H19 and Igf2. Analysis of
allele-specific expression of H19 and Igf2 and DNA
methylation at the H19 promoter demonstrates that this region controls the monoallelic expression of the two genes in different ways,
suggesting that it harbors two functionally distinct regulatory elements. Continued presence of the region is required to silence maternal Igf2 in accordance with its proposed role as an
insulator. However, it does not have a direct role in keeping the
paternal H19 promoter silenced. Instead, on the paternal
chromosome, the upstream element mediates epigenetic modifications of
the H19 promoter region during development, leading to
transcriptional silencing of H19. Thereafter, its presence is
redundant for preventing transcription. Presently, this temporal
requirement of the silencing element appears to be a unique cis
activity in the mammalian system. However, it is likely that other
cis-acting elements, positive and negative, have the ability to
effect stable changes in the chromatin structure and are not constantly
required to give signals to the transcriptional machinery.
[Key Words: Genomic imprinting; conditional deletion; DMR; H19; Igf2]
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