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Molecular and Cellular Biology, December 2001, p. 8189-8196, Vol. 21, No. 23
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.23.8189-8196.2001

Regulatory Mechanisms at the Mouse Igf2/H19 Locus

Christopher R. Kaffer, Alex Grinberg, and Karl Pfeifer*

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.

* 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.

Molecular and Cellular Biology, December 2001, p. 8189-8196, Vol. 21, No. 23
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.23.8189-8196.2001


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