International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

A6 The Mechanisms of Gene Silencing in Genomic Imprinting

Amy T. Hark, Christopher J. Schoenherr, David Katz, Michele A. Cleary and Shirley M. Tilghman. Howard Hughes Medical Institute and Department of Molecular Biology, Princeton University, Princeton NJ 08544

Genomic imprinting is an unusual transcriptional phenomenon because it results in the silencing of autosomal genes in a parent-specific manner. The specificity is achieved by the imposition of epigenetic marks that are established in the gametes, and then sustained throughout development. One epigenetic mark, DNA methylation, has been functionally shown to be responsible for silencing a number of imprinted genes, for example the mouse H19 gene. However a second class of imprinted genes like the Igf2 gene requires the presence of DNA methylation for its expression. We have proposed that this contradiction is explained by the presence of a chromatin boundary downstream of the Igf2 gene that blocks its access to enhancers Igf2 on the maternal chromosome where Igf2 is silent. On the paternal chromosome this region of DNA is heavily methylated, which presumably results in the inactivation of the boundary, and the expression of Igf2. The methylation also silences the H19 gene, thus the element is bi-functional for gene silencing. We have confirmed this model by transfection studies in cell culture and in transgenic mice. Igf2 and H19 are tightly linked to a second cluster of maternally expressed genes that includes Mash2, Kvlqt1 and p57Kip2. We have previously shown that the mechanism that mediates the imprinting of Igf2 and H19 does not operate on those genes. To ask whether these genes constitute an imprinting "operon", we used cre-lox technology to generate a translocation that separated Mash2 and Kvlqt1 from p57Kip2. Surprisingly the imprinting of all three genes, as well as Igf2 and H19 was unaffected, suggesting that the genes in this cluster are independently regulated by imprinting.


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