KRAB zinc finger protein SNERV is required to repress non-ecotropic murine endogenous retroviruses and underlies the Sgp3 and Gv1 loci

Transcriptional silencing of proviral endogenous retrovirus (ERV) elements serves as a critical layer of defense from active retrotransposition and disease. However, a specific repressor responsible for silencing non-ecotropic ERV (NEERV) loci in mice has not yet been identified. In this study, we identified Suppressor of non-ecotropic ERV (Snerv), a KRAB-ZFP gene responsible for NEERV repression that is present in C57BL/6J but not in C57BL/6N mice. SNERV targets the PBSGln sequence within the NEERV LTR and recruits the transcriptional regulator KAP1. Germline homozygous deletion of Snerv leads to increased activating chromatin modifications at NEERV loci, elevated NEERV mRNA transcription, and increased cell surface expression of NEERV protein. The F1 cross with wild type, but not Snerv-/- C57BL/6 mice, repressed NEERV overexpression in NZB and 129 mice, thus mapping the long sought-after Sgp3 and Gv1 loci to Snerv.