PiRNAs Can Trigger a Multigenerational Epigenetic Memory in the Germline of C. elegans

Alyson Ashe,Alexandra Sapetschnig,Eva-Maria Weick,Jacinth Mitchell,Marloes P Bagijn,Amy C Cording,Anna-Lisa Doebley,Leonard D Goldstein,Nicolas J Lehrbach,Jérémie Le Pen,Greta Pintacuda,Aisa Sakaguchi,Peter Sarkies,Shawn Ahmed,Eric A Miska

doi:10.1016/j.cell.2012.06.018

Abstract

SummaryTransgenerational effects have wide-ranging implications for human health, biological adaptation, and evolution; however, their mechanisms and biology remain poorly understood. Here, we demonstrate that a germline nuclear small RNA/chromatin pathway can maintain stable 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 is required for multigenerational inheritance of environmental RNAi and piRNA silencing. These include a germline-specific nuclear Argonaute HRDE1/WAGO-9, a HP1 ortholog HPL-2, and two putative histone methyltransferases, SET-25 and SET-32. 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 a multigenerational epigenetic inheritance mechanism induced by piRNAs.

Highlights

Since August Weismann (1834–1914) formulated the distinction between innate and acquired characteristics at the end of the 19th century, the debate relating to the inheritance of acquired traits has raised many controversies in the scientific community (Weismann, 1891; Bateson, 1919; Haig, 2006)
We demonstrate that a germline nuclear small RNA/chromatin pathway can maintain stable inheritance for many generations when triggered by a Piwi-interacting RNAs (piRNAs)-dependent foreign RNA response in C. elegans
Using forward genetic screens and candidate approaches, we find that a core set of nuclear RNA interference (RNAi) and chromatin factors is required for multigenerational inheritance of environmental RNAi and piRNA silencing

Summary

SUMMARY

Transgenerational effects have wide-ranging implications for human health, biological adaptation, and evolution; their mechanisms and biology remain poorly understood. Using forward genetic screens and candidate approaches, we find that a core set of nuclear RNAi and chromatin factors is required for multigenerational inheritance of environmental RNAi and piRNA silencing. These include a germline-specific nuclear Argonaute HRDE1/ WAGO-9, a HP1 ortholog HPL-2, and two putative histone methyltransferases, SET-25 and SET-32. 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 a multigenerational epigenetic inheritance mechanism induced by piRNAs

INTRODUCTION

RESULTS

20 P0 antisense 20

DISCUSSION

EXPERIMENTAL PROCEDURES