A nuclear Argonaute promotes multigenerational epigenetic inheritance and germline immortality

Abstract

Epigenetic information is frequently erased near the start of each new generation (1). In some cases, however, epigenetic information can be transmitted from parent to progeny (epigenetic inheritance) (2). A particularly striking example of epigenetic inheritance is dsRNA-mediated gene silencing (RNAi) in C. elegans, which can be inherited for more than five generations (3–8). To understand this process we conducted a genetic screen for animals defective for transmitting RNAi silencing signals to future generations. This screen identified the gene heritable RNAi defective (hrde)-1. hrde-1 encodes an Argonaute (Ago) that associates with small interfering (si)RNAs in germ cells of the progeny of animals exposed to dsRNA. In nuclei of these germ cells, HRDE-1 engages the Nrde nuclear RNAi pathway to direct H3K9me3 at RNAi targeted genomic loci and promote RNAi inheritance. Under normal growth conditions, HRDE-1 associates with endogenously expressed siRNAs, which direct nuclear gene silencing in germ cells. In hrde-1 or nuclear RNAi deficient animals, germline silencing is lost over generational time. Concurrently, these animals exhibit steadily worsening defects in gamete formation and function that ultimately lead to sterility. These results establish that the Ago HRDE-1 directs gene-silencing events in germ cell nuclei, which drive multi-generational RNAi inheritance and promote immortality of the germ cell lineage. We propose that C. elegans uses the RNAi inheritance machinery to transmit epigenetic information, accrued by past generations, into future generations to regulate important biological processes.

Guest list or black list: heritable small RNAs as immunogenic memories

“…Moreover, HRDE-1 is found in oocytes nuclei but not in differentiated sperm nuclei [27], although RNAi is most efficiently transmitted via sperm [17]. In summary, HRDE-1 and NRDE proteins are important for consolidation of the inherited response, which is triggered by small RNAs, and established by chromatin remodeling [6,27].…”

“…The inherited effect of RNAi on chromatin was shown to be mediated by HRDE-1 (heritable RNAi defective-1, also named WAGO-9; for Worm Specific Argonaute 9) and Nuclear RNAi factors (NRDEs, for Nuclear RNAi Defective). HRDE-1 is a germline-expressed Argonaute protein that binds secondary siRNAs, and while it is required for efficient RNAi inheritance, it is dispensable for RNAi per se [26][27][28]. HRDE-1 and NRDE proteins probably function in consolidating transgenerational RNAi "memory", rather than in the actual shuttling of the heritable RNA agent across generations.…”

“…HRDE-1 and NRDE proteins probably function in consolidating transgenerational RNAi "memory", rather than in the actual shuttling of the heritable RNA agent across generations. Indeed, HRDE-1 and NRDE mutant parents are still capable of transmitting RNAi to their progeny, while mutant progeny is incapable of establishing RNAi using the inherited small RNAs received from wild-type parents [23,27,29]. Moreover, Rechavi…”

“…Indeed, HRDE-1 and NRDE mutant parents are still capable of transmitting RNAi to their progeny, while mutant progeny is incapable of establishing RNAi using the inherited small RNAs received from wild-type parents [23,27,29]. Moreover, HRDE-1 is found in oocytes nuclei but not in differentiated sperm nuclei [27], although RNAi is most efficiently transmitted via sperm [17]. In summary, HRDE-1 and NRDE proteins are important for consolidation of the inherited response, which is triggered by small RNAs, and established by chromatin remodeling [6,27].…”

“…A number of groups have now shown that heritable worm PRG-1-bound piRNAs (a worm PIWI protein) scan and silence foreign elements by inducing chromatin remodeling in the germline [26][27][28]41]. One group suggested that small RNAs, which are bound by different Argonaute proteins, serve as epigenetic memories of "self" and "nonself" RNAs.…”