The MOV10 RNA helicase is a dosage-dependent host restriction factor for LINE1 retrotransposition in mice

Abstract

Transposable elements constitute nearly half of the mammalian genome and play important roles in genome evolution. While a multitude of both transcriptional and post-transcriptional mechanisms exist to silence transposable elements, control of transposition in vivo remains poorly understood. MOV10, an RNA helicase, is a potent inhibitor of mobilization of retrotransposons and retroviruses in cell culture assays. Here we report that MOV10 restricts LINE1 retrotransposition in mice. Although MOV10 is broadly expressed, its loss causes only incomplete penetrance of embryonic lethality, and the surviving MOV10-deficient mice are healthy and fertile. Biochemically, MOV10 forms a complex with UPF1, a key component of the nonsense-mediated mRNA decay pathway, and primarily binds to the 3' UTR of somatically expressed transcripts in testis. Consequently, loss of MOV10 results in an altered transcriptome and a modest upregulation of two LINE1 families in testis. Analyses using a LINE1 reporter transgene reveal that loss of MOV10 leads to increased LINE1 retrotransposition in somatic and reproductive tissues from both embryos and adult mice. Moreover, the degree of LINE1 retrotransposition inhibition is dependent on the Mov10 gene dosage. Furthermore, MOV10 deficiency reduces reproductive fitness over successive generations. Our findings demonstrate that MOV10 attenuates LINE1 retrotransposition in a dosage-dependent manner in mice.

Transposon-mediated genic rearrangements underlie variation in small RNA pathways

“…Depending on the genomic and environmental contexts, genetic variation favoring one or the other primary siRNA pathway could have been selected [39][40][41][42] . Research in mammals has shown the importance of dosage of the orthologous MOV10 helicase on retrovirus silencing 43 . We showed here that natural structural variants at the eri-6/7 locus were a major driver of variation in ERGO-1 pathway activity and mRNA levels of its downstream regulated showing the most divergent eri-6/7 region based on SNVs (Fig.…”