IMPRINTING OF HUMAN H19 - ALLELE-SPECIFIC CPG METHYLATION, LOSS OF THE ACTIVE ALLELE IN WILMS-TUMOR, AND POTENTIAL FOR SOMATIC ALLELE SWITCHING

Genomic imprinting and monoallelic gene expression appear to play a ro le in human genetic disease and tumorigenesis. The human H19 gene, at chromosome 11p15, has previously been shown to be monoallelically expr essed. Since CpG methylation has been implicated in imprinting, we ana lyzed methylation of H19 DNA. In fetal and adult organs the transcript ionally silent H19 allele was extensively hypermethylated through the entire gene and its promoter, and, consistent with a functional role f or DNA methylation, expression of an H19 promoter-reporter construct w as inhibited by in vitro methylation. Gynogenetic ovarian teratomas we re found to contain only hypomethylated H19 DNA, suggesting that the e xpressed H19 allele might be maternal. This was confirmed by analysis of 11p15 polymorphisms in a patient with Wilms tumor. The tumor had lo st the maternal 11p15, and H19 expression in the normal kidney was exc lusively from this allele. Imprinting of human H19 appears to be susce ptible to tissue-specific modulation in somatic development; in one in dividual, cerebellar cells were found to express only the otherwise si lent allele. Implications of these findings for the role of DNA methyl ation in imprinting and for H19 as a candidate imprinted tumor-suppres sor gene are discussed.