AGO2 silences mobile transposons in the nucleus of quiescent cells [ChIP-seq]

Argonaute 2 (AGO2) is a cytoplasmic component of the miRNA pathway with essential roles in development and disease. Yet, little is known about its regulation in vivo. Here, we show that in mouse quiescent cells, AGO2 localizes almost exclusively to the nucleus. In quiescent splenocytes, AGO2's subcellular localization is modulated by the Pi3K-AKT-mTOR pathway, a well-established regulator of quiescence. Signaling through this pathway in proliferating cells promotes AGO2 cytoplasmic accumulation at least in part by stimulating the expression of TNRC6, an AGO2 binding partner in the miRNA pathway. In contrast, low signaling in quiescent cells enables AGO2 to accumulate in the nucleus where it binds to young mobile transposons co-transcriptionally. Loss of AGO2 in quiescent cells results in upregulation of transposon transcripts suggesting it performs functions analogous to those of PIWI in the germline. Our results point to an essential but previously unrecognized nuclear role for AGO2 during mammalian quiescence as part of a genome-defense system against transposable elements. Overall design: Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for HA epitope in freshly isolated splenic B cells from wild-type (control) or Ago2HA/HA mice. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for H3K9me3 in splenic B cells from wild-type, Ago2+/flx, and Ago2ADH/flx mice following CRE-mediated recombination. Please note that the additional samples (GSM6351517, GSM6351518 included on July 19th, 2022) are exactly the same samples as GSM6152936, GSM6152938. However, they have been re-sequenced with Paired-end sequencing.