Aberrant tissue specific expression of the transgene in transgenic mice that carry the hepatitis B virus genome defective in the X gene.
The control mechanisms for the transgene expression in mice that carry the hepatitis B virus genome defective in the polymerase and X genes were analyzed. Ten lines of transgenic mouse were established, and in seven lines the surface and e antigens were detected in the serum. In transgenic mice from five lines examined, the transgene was markedly expressed in a broad spectrum of tissues including the kidney, heart, brain, muscle and intestine, but only poorly in the liver. In the kidney and heart the 3.5 kb and 2.1 kb mRNAs were expressed, whereas only the 0.8 kb and 4.0 kb mRNAs were detected in the testis and brain, respectively, suggesting that each of the mRNAs was transcribed through a different control mechanism. The surface, e and core antigens accumulated in the kidney and heart. DNA was hypomethylated at a region closely downstream of the enhancer in the liver, kidney and heart, and a DNase I hypersensitive site was detected upstream of the enhancer in these tissues. In the testis, however, the whole transgene was hypomethylated and the DNase I hypersensitive site was closer to the enhancer. These differences may be relevant to the preferential expression of the 0.8 kb mRNA in the testis, but cannot explain the inefficiency of transgene expression in the liver. Our observations suggest that the X protein is required for efficient expression of the viral gene in the liver but not in other tissues.
Institute of Medical Science, University of Toyko, Japan.
H
H
Nagashima
M
M
Imai
Y
Y
Iwakura
D000818:Animals; D015254:DNA Modification Methylases / Q000378:metabolism; D003850:Deoxyribonuclease I / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D015967:Gene Expression Regulation, Viral; D016679:Genome, Viral; D006514:Hepatitis B Surface Antigens / Q000097:blood; D006513:Hepatitis B e Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000235:genetics*; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014018:Tissue Distribution; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D054334:Viral Regulatory and Accessory Proteins
D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D012333:RNA, Messenger; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D015254:DNA Modification Methylases; D003850:Deoxyribonuclease I