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 role in human genetic disease and tumorigenesis. The human H19 gene, at chromosome 11p15, has previously been shown to be monoallelically expressed. Since CpG methylation has been implicated in imprinting, we analyzed methylation of H19 DNA. In fetal and adult organs the transcriptionally silent H19 allele was extensively hypermethylated through the entire gene and its promoter, and, consistent with a functional role for DNA methylation, expression of an H19 promoter-reporter construct was inhibited by in vitro methylation. Gynogenetic ovarian teratomas were found to contain only hypomethylated H19 DNA, suggesting that the expressed H19 allele might be maternal. This was confirmed by analysis of 11p15 polymorphisms in a patient with Wilms tumor. The tumor had lost the maternal 11p15, and H19 expression in the normal kidney was exclusively from this allele. Imprinting of human H19 appears to be susceptible to tissue-specific modulation in somatic development; in one individual, cerebellar cells were found to express only the otherwise silent allele. Implications of these findings for the role of DNA methylation in imprinting and for H19 as a candidate imprinted tumor-suppressor gene are discussed.
Department of Pathology, Columbia University, New York, NY 10032.
Y
Y
Zhang
T
T
Shields
T
T
Crenshaw
Y
Y
Hao
T
T
Moulton
B
B
Tycko
D000328:Adult; D000483:Alleles; D001483:Base Sequence; D002880:Chromosomes, Human, Pair 11; D004273:DNA, Neoplasm / Q000378:metabolism; D015226:Dinucleoside Phosphates / Q000378:metabolism*; D005260:Female; D005333:Fetus; D006801:Humans; D008745:Methylation; D008969:Molecular Sequence Data; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D013724:Teratoma / Q000235:genetics / Q000378:metabolism; D009396:Wilms Tumor / Q000235:genetics*
D004273:DNA, Neoplasm; D015226:Dinucleoside Phosphates; C015772:CpG dinucleotide