GSE121640
The KRAB zinc finger protein SNERV represses proviral endogenous retroviruses and underlies the Sgp3 and Gv1 loci
Transcriptional silencing of endogenous retroviruses (ERV) defends against active retrotransposition and disease, including overproduction of non-ecotropic ERV (NEERV) envelope and resultant nephritis observed in lupus-prone mice. However, a repressor targeting NEERV loci has not yet been identified. In this study, we identified suppressor of NEERV (Snerv), a Krüppel-associated box zinc finger protein gene responsible for NEERV repression in multiple inbred mouse strains. We show that SNERV binds to the NEERV long terminal repeat and recruits the transcriptional regulator KAP1. Germline deletion of Snerv leads to increased activating chromatin modifications, transcription, and expression of envelope glycoprotein, gp70, from NEERV loci. We found that the NZB and 129 genomes, which overexpress NEERV gp70, cannot rescue defective NEERV repression in F1 crosses to Snerv-/- mice, thus mapping the long sought-after Sgp3 and Gv1 loci to Snerv and demonstrating that loss of SNERV is responsible for the overexpression of the lupus autoantigen gp70. We also found elevated expression of human ERV transcripts in lupus patients compared to healthy controls, and identify putative KRAB-ZFP genes whose expression inversely correlates with human ERV levels. Collectively, our study highlights a role for the KRAB-ZFP, Snerv, in mouse NEERV repression, and suggests similar ERV dysregulation in human lupus disease. Overall design: Paired-end RNAseq and ChIPseq of various immune tissues comparing B6N to B6J mice Please note that BioProject PRJNA482844 (SRA submission SUB4310516) contains all of our whole genome sequencing data for this same study.