GSE38813
piRNAs can trigger a multigenerational epigenetic memory in the germline of C. elegans
Transgenerational effects likely have wide-ranging implications for human health, biological adaptation and evolution, however their mechanism and biology remain poorly understood. Here we demonstrate that a germline nuclear small RNA/chromatin pathway can maintain epi-allelic inheritance for many generations when triggered by a piRNA-dependent foreign RNA response in C. elegans. Using forward genetic screens and candidate approaches we find that a core set of nuclear RNAi and chromatin factors are required for multigenerational inheritance of environmental RNAi and piRNA silencing. These include a germline-specific nuclear Argonaute HRDE1/WAGO-9, a HP1 otholog HPL-2 and two putative histone methyltransferases, SET-25 and SET-32. Most surprisingly, piRNAs can trigger highly stable long-term silencing lasting at least 20 generations. Once established, this long-term memory becomes independent of the piRNA trigger but remains dependent on the nuclear RNAi/chromatin pathway. Our data present the first report of multigenerational epigenetic inheritance induced by piRNAs in any organism. Overall design: Seven C. elegans small RNA libraries from three distinct experiments (A, B, C) were sequenced using Illumina sequencing technology. Five small RNA libraries were prepared according to library construction protocol 1 and sequenced as part of 22 flow cell lanes on the Illumina GA IIx platform. Samples were labelled for multiplexing using 4-bp 5'-barcodes, a single flow cell lane included several multiplexed libraries. Two small RNA libraries were prepared according to library construction protocol 2 and sequenced on the Illumina MiSeq platform.