Stress resets ancestral heritable small RNA responses

Abstract

Transgenerational inheritance of small RNAs challenges basic concepts of heredity. In C. elegans nematodes, small RNAs are transmitted across generations to establish a transgenerational memory trace of ancestral environments and distinguish self-genes from non-self-elements. Carryover of aberrant heritable small RNA responses was shown to be maladaptive and to lead to sterility. Here we show that various types of stress (starvation, high temperatures, and high osmolarity) induce resetting of ancestral small RNA responses and a genome-wide reduction in heritable small RNA levels. We found that mutants that are defective in various stress pathways exhibit irregular RNAi inheritance dynamics even in the absence of stress. Moreover, we discovered that resetting of ancestral RNAi responses is specifically orchestrated by factors that function in the p38 MAPK pathway and the transcription factor SKN-1/Nrf2. Stress-dependent termination of small RNA inheritance could protect from run-on of environment-irrelevant heritable gene regulation.

Diversification of small RNA pathways underlies germline RNAi incompetence in wild C. elegans strains

“…RNAi is a complex and intricate collection of phenomena. RNAi responses are sensitive to environmental conditions (Houri-Zeevi et al, 2021) and susceptible to unexpected outcomes (De-Souza et al, 2019), which in turn could be mediated differently in different genetic backgrounds.…”

“…However, the extent of condition-dependent interactions in RNAi may preclude true experimental control. For example, temperature likely plays an unseen hand in RNAi experimentation, given the exquisite sensitivity of C. elegans to temperature (Testa et al, 2020) and the intimate relationship between temperature and other stresses and RNAi (Frézal et al, 2018;Houri-Zeevi et al, 2021;Pagliuso et al, 2021). We controlled environmental temperature by conducting all RNAi assays at 20°C, but RNAi competence may be maximized at different temperatures in different strains.…”

“…On the other hand, temperature may be used to uncover plastic and adaptive responses (Paaby & Testa, 2018). In this system, which increasingly appears to be dominated by transgenerationally inherited small RNA programs (Houri-Zeevi et al, 2021), temperature may prove a valuable tool in exposing the variability and function of C. elegans inheritance systems in the wild (Frézal et al, 2018).…”

“…Another possibility is that in the wild, RNAi in the germline matters most to future generations. Strains resistant to RNAi upon exposure can show transgenerational sensitivity ( Tijsterman et al, 2002 ), and a growing body of research emphasizes the outsized role of RNAi in transgenerational inheritance ( Houri-Zeevi et al, 2020, 2021). Thus, RNAi as we have studied it in the lab provides an oblique view into its role in nature.…”

“…C. elegans increasingly appears to be dominated by transgenerationally inherited small RNA programs ( Houri-Zeevi et al, 2020, 2021) that vary significantly in nature ( Frézal et al, 2018 ). This variation offers leverage: characterization of wild-type variation can elucidate condition-dependent mechanisms ( Chandler et al, 2013 ), which are rampant in RNAi, a complex and intricate collection of interactions susceptible to unexpected outcomes ( De-Souza et al, 2019 ) and sensitive to environmental conditions ( Houri-Zeevi et al, 2021 ). Identifying mechanisms of variation will help to bridge the gulf between our understanding of the genetics of RNAi and the role of RNAi in nature, and future work may benefit from evaluating wild-type isolates in the context of carefully chosen environmental perturbations ( Rockman, 2008 ).…”