Nature Genetics
7, 433 - 439 (1994)
doi:10.1038/ng0794-433
Loss of imprinting of IGF2 is linked to reduced expression and abnormal methylation of H19 in Wilms' tumourMarja J. C. Steenman1, Shirley Rainier1, Craig J. Dobry1, Paul Grundy2, Isabelle L. Horon3
& Andrew P. Feinberg1, 4, 5
1Howard Hughes Medical Institute and Departments of Internal Medicine and Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
2Cross Cancer Institute, Molecular Oncology Program, Room 3337, 11560 University Avenue, Edmonton, Alberta, Canada T6G 1Z2
3Maryland Center for Health Statistics, Room 544, 201 W. Preston St., Baltimore, Maryland 21201, USA
4Departments of Medicine, Molecular Biology & Genetics, and Oncology, Johns Hopkins University School of Medicine, 1064 Ross, 720 Rutland Avenue, Baltimore, Maryland 21205, USA
5Correspondence should be addressed to A.P.F. The insulin−like growth factor−II (IGF2) and H19 genes are imprinted in mouse and human, with expression of the paternal IGF2 and maternal H19 alleles. IGF2 undergoes loss of imprinting (LOI) in most Wilms' tumours (WT). We now show that: (i) LOI of IGF2 is associated with a 80−fold down regulation of H19 expression; (ii) these changes are associated with alterations in parental−origin−specific, tissue−independent sites of DNA methylation in the H19 promoter; and (iii) loss of heterozygosity is also associated with loss of H19 expression. Thus, imprinting of a large domain of the maternal chromosome results in a reversal to a paternal epigenotype. These data also suggest an epigenetic mechanism for inactivation of H19 as a tumour suppressor gene.
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