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Molecular and Cellular Biology, December 2001, p. 8189-8196, Vol. 21, No. 23
Laboratory of Mammalian Genes and
Development, National Institute of Child Health and Human Development,
Bethesda, Maryland 20892
Received 23 May 2001/Returned for modification 19 July
2001/Accepted 28 August 2001
The closely linked H19 and Igf2 genes show
highly similar patterns of gene expression but are reciprocally
imprinted. H19 is expressed almost exclusively from the
maternally inherited chromosome, while Igf2 expression is
mostly from the paternal chromosome. In humans, loss of imprinting at
this locus is associated with tumors and with developmental disorders.
Monoallelic expression at the imprinted Igf2/H19 locus
occurs by at least two distinct mechanisms: a developmentally regulated
silencing of the paternal H19 promoter, and transcriptional
insulation of the maternal Igf2 promoters. Both mechanisms
of allele-specific silencing are ultimately dependent on a common
cis-acting element located just upstream of the
H19 promoter. The coordinated expression patterns and some experimental data support the idea that positive regulatory elements are also shared by the two genes. To clarify the organization and
function of positive and negative regulatory elements at the H19/Igf2 locus, we analyzed two mouse mutations. First, we
generated a deletion allele to localize enhancers used in vivo for
expression of both H19 and Igf2 in mesodermal
tissues to sequences downstream of the H19 gene.
Coincidentally, we demonstrated that some expression of
Igf2 is independent of the shared enhancer element. Second, we used this new information to further characterize an ectopic H19 differentially regulated region and the associated
insulator. We demonstrated that its activity is parent-of-origin
dependent. In contrast to recent results from Drosophila
model systems; we showed that this duplication of a mammalian insulator
does not interfere with its normal function. Implications of these
findings for current models for monoallelic gene expression at this
locus are discussed.
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.23.8189-8196.2001
Regulatory Mechanisms at the Mouse
Igf2/H19 Locus
*
Corresponding author. Mailing address: 9000 Rockville
Pike, Building 6B, Room 2B206, NICHD, Bethesda, MD 20892. Phone: (301) 402-0676. Fax: (301) 402-0543. E-mail:
kpfeifer{at}helix.nih.gov.
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