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  1. Reviewer #3 (Public Review):

    In the paper entitled "Stress Resets Transgenerational Small RNA Inheritance" Houri-Ze'evi L, Teichman G et al examine the interaction between multiple heritable phenotypes by knocking down a heritable GFP reporter and examining its interaction with other stresses, such as starvation and high temperature, which cause transgenerationally heritable phenotypes. They demonstrate that exposing worms to stresses inhibits the transgenerational silencing of the GFP reporter strain they use. They further demonstrate that deletion of genes involved in the MAPK pathway, the skn-1 transcription factor and the putative H3K9 methyltranferase met-2 eliminate the differential response in the F1 and F2 generations after exposure to stress and the GFP reporter silencing. They also sequence the small RNAs in the P0 and F1 generation with and without the added stresses.

    All in all, the authors have expanded the mechanistic understanding of how heritable small RNAs are influenced by environmental conditions. I think that the conservation of several of the known regulators of epigenetic inheritance appearing in this study reflects how the regulators of non-genetic inheritance are beginning to converge on a few central pathways. The bit about MET-2 is still a bit premature as it's link to SKN-1 and regulated small RNAs is not completely fleshed out here, but I'm sure future studies will help delineate how this putative methyltransferase is communicating with SKN-1 on a more mechanistic level. Future studies examining how and why the MAPK pathway is so critical in this inheritance paradigm will be interesting.

  2. Reviewer #2 (Public Review):

    In humans, extreme stresses, such as famine, can trigger multi-generational physiological responses through altered metabolism. In C. elegans, environmental stresses, such as heat shock, can similarly promote changes in gene expression and physiology. In addition, researchers observed more than two decades ago that dsRNA triggers can silence gene expression transgenerationally. This manuscript by Houri-Zeevi et al., entitled "Stress resets ancestral heritable small RNA responses", seeks to tie these two observations in C. elegans together mechanistically, showing that environmental stress (heat shock, high osmolarity, or starvation) can alter the small RNA populations in adults and their progeny, affecting their gene expression levels. The authors used a GFP reporter as a proxy for exo-siRNA levels in various experimental paradigms. P0 animals were fed dsRNA targeting the GFP transgene, and their F1 progeny were subjected to one of the environmental stresses. The GFP expression levels of P0, F2, and F2 adults were measured, showing that the stressed F1 and their F2 progeny have increased de-silencing of the GFP transgene compared to controls. The authors also performed small RNA sequencing on these populations, showing that a subset of small RNAs become "reset" or decreased after stress, while a different subset was increased. Additionally, the p38 MAPK pathway, SKN-1 TF, and MET-2 H3K4me1/2 HMT were shown to be required for the stress-dependent changes in transgene de-silencing. The manuscript is well-written and contains some very interesting and convincing results that should be of broad interest to the fields of stress biology and RNAi.

  3. Reviewer #1 (Public Review):

    Here, Houri-Ze'evi, et al. treated progeny of parents that had inherited small RNA response (silencing of an artificial, single-copy GL-expressed gfp with anti-gfp dsRNA) with 3 stresses – heat shock, hyperosmolarity, or starvation – starting at L1, and examined gfp silencing. All three treatments reduced silencing (visible as increased GFP fluorescence) in subsequent generations (F1-F3). The authors tested resetting of endogenous (endo-siRNA) and piRNAs using an endo-siRNA sensor target sequence and piRNA recognition sites, respectively. Again, all 3 stressors reset both in the same generation, but did not reset the effect transgenerationally, suggesting that exogenous RNAi resetting functions through a different mechanism than endogenous.

    Next, they tested adults, which also led to resetting. However, only the F1 generation, not F2, is susceptible to resetting (how? Why?), revealing a critical period for resetting susceptibility. Reversal of the stress with RNAi treatment does not result in resetting, nor does simpy changing conditions. The authors then went on to examine mutants that might be defective in stress responses or in resetting; MAPK genes and skn-1 are required for resetting. Small RNA-seq from stressed worms and their progeny showed a decrease overall with stresses, and reveals some potential classes of genes, including targets of the mutator genes, and overlap with classic stress response pathways (dauer, IIS). Overall, this work presents some interesting phenomena and moves towards explaining how it might work through the identification of a critical period and some genes that are required.

    In this version, the authors have added more information regarding the relationship between MAPK and SKN-1, and transcriptional targets. Most importantly, they have performed tissue-specific rescue of sek-1; in neurons, this rescues, but intestine did not.

    These data add to prior work from the Rechavi lab and others in the field, which together address the interplay of small RNAs, response to stress, and transgenerational inheritance.

  4. Evaluation Summary:

    In humans, extreme stresses, such as famine, can trigger multi-generational physiological responses through altered metabolism. In C. elegans, environmental stresses, such as heat shock, can similarly promote changes in gene expression and physiology. Here, the authors convincingly show that environmental stress can alter small RNA populations in such a manner that can alter gene expression over multiple generations. The work is beginning to tease out some of the mechanisms by which non-genetic information can regulate descendants biology.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

  5. Excerpt

    Houri-Ze’evi and colleagues demonstrate that exposure to stress disrupts inheritance of RNAi responses established in the previous generation.