CONTROL OF EXPRESSION AND METHYLATION OF A HEPATITIS-B VIRUS TRANSGENE BY STRAIN-SPECIFIC MODIFIERS

In transgenic animals, genotype-specific modifiers exert a control ove r transgene methylation and expression that may or may not be position dependent. These factors belong to different classes, some of them po ssibly related to modifiers of position-effect variegation in Drosophi la. The study of hepatitis B virus (HBV) gene expression in transgenic mice has revealed the existence of many factors influencing transcrip tion, including hormones and tissue-specific transcription factors. We now report the effect of genotype-specific modifiers on HBV surface a ntigen (HBsAg) expression and transgene methylation, Compared with the C57BL/6 background, the DBA/2 and 129sv backgrounds cause enhancement of HBsAg expression, with little or not effect on transgene methylati on or transcription. In contrast, a single cross with a BALB/c mouse i s responsible for de novo methylation and silencing of the transgene i n ail offspring. Several modifiers appear to segregate in the progeny of a transgenic E36 male mouse crossed with (C57BL/6 x BALB/c) F-1 fem ales, with the emergence of a high-expressor group. Our observations s uggest that different modifiers act cooperatively, at both the transcr iptional and post-transcriptional levels, as part of a complex system regulating transgene expression. This transgenic model provides a syst em to genetically map new mouse strain-specific modifiers, some of the m involved in epigenetic modification and transcription control.