Biallelic expression of the H19 gene during spontaneous hepatocarcinogenesis in the albumin SV40 T antigen transgenic rat.
Previous studies in this laboratory have demonstrated that the earliest cytogenetic alteration in the development of hepatic neoplasms in a transgenic strain of rats bearing the albumin Simian virus 40 T antigen (Alb SV40 T Ag) construct was a duplication of the chromosome 1q4.1-1q4.2 band. In this region, in the rat genome a cluster of linked imprinted genes occurs. One of these imprinted genes, H19, which is expressed in fetal liver but not in adult liver, was found to be expressed in virtually all neoplasms investigated. A single-nucleotide polymorphic marker in the H19 coding sequence was identified in two rat strains and utilized for the investigation of H19 imprinting. Our results reveal monoallelic expression of the maternal gene in fetal liver, but biallelic expression of the H19 gene in liver neoplasms, thus demonstrating the basis for the deregulation of the imprinted gene expression during hepatocarcinogenesis. These results suggest that the loss of genomic imprinting of the H19 gene found in the liver neoplasms of the Alb SV40 T Ag rat may result not from allelic loss, but from adverse changes in the epigenetic imprints present in the 5'-upstream region of the H19 promoter of the parental alleles.
Manoharan
Herbert
H
McArdle Laboratory for Cancer Research, Medical School, University of Wisconsin, Madison, Wisconsin, USA.
Babcock
Karlee
K
Willi
Jonathan
J
Pitot
Henry C
HC
D000418:Albumins / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015870:Gene Expression / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis / Q000235:genetics; D008114:Liver Neoplasms, Experimental / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017422:Sequence Analysis, DNA
D000418:Albumins; D000952:Antigens, Polyomavirus Transforming; C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D007335:Insulin-Like Growth Factor II