The Sgp3 locus derived from the 129 strain is responsible for enhanced endogenous retroviral expression in macroH2A1-deficient mice

Abstract

The endogenous retroviral envelope glycoprotein, gp70, implicated in murine lupus nephritis is secreted by hepatocytes, and its expression is largely regulated by the Sgp3 ( serum gp70 production 3) locus derived from lupus-prone mice. Because of the localization of the macroH2A1 gene encoding macroH2A histone variants within the Sgp3 interval and of an up-regulated transcription of endogenous retroviral sequences in macroH2A1-deficient C57BL/6 (B6) mice, we investigated whether macroH2A1 is a candidate gene for Sgp3. macroH2A1-deficient B6 mice carrying the 129-derived Sgp3 locus, which was co-transferred with the 129 macroH2A1 mutant gene, displayed increased levels of serum gp70 and hepatic retroviral gp70 RNAs comparable to those of B6.NZB- Sgp3 congenic mice bearing the Sgp3 locus of lupus-prone NZB mice. In contrast, the abundance of retroviral gp70 RNAs in macroH2A1-deficient 129 mice was not elevated at all as compared with wild-type 129 mice. Furthermore, Sgp3 subcongenic B6 mice devoid of the NZB-derived macroH2A1 gene displayed an Sgp3 phenotype identical to that of B6.NZB- Sgp3 congenic mice carrying the NZB-derived macroH2A1 gene, thus excluding macroH2A1 as a candidate Sgp3 gene. Collectively, our data indicate that enhanced transcription of endogenous retroviral sequences observed in macroH2A1-deficient B6 mice is not a result of the macroH2A1 mutation, but due to the presence of the 129-derived Sgp3 locus. In contrast, the effect of a macroH2A1 knockout mutation on the expression of several non-retroviral cellular genes was very similar on the B6 and 129 backgrounds, indicating that these effects were due to the macroH2A1 knockout.