Stress Resets Transgenerational Small RNA Inheritance

Abstract

Transgenerational inheritance of small RNAs is challenging basic concepts of heredity and achieving control over such responses is of great interest. In C. elegans nematodes, small RNAs are transmitted across generations to establish a transgenerational memory trace of ancestral environments and distinguish self from non-self genes. Inheritance of small RNAs is regulated by dedicated machinery and carryover of aberrant heritable small RNA responses was shown to be maladaptive and to induce sterility. Here we show that various types of stress (starvation, high temperatures, and high osmolarity) but not non-stressful changes in cultivation conditions, lead to resetting of small RNA inheritance. We found that stress leads to a genome-wide reduction in heritable small RNA levels and that mutants defective in different stress pathways exhibit irregular RNAi inheritance dynamics. Moreover, we discovered that resetting of heritable RNAi is orchestrated by MAPK pathway factors, the transcription factor SKN-1, and the MET-2 methyltransferase. Termination of small RNA inheritance, and the fact that this process depends on stress, could protect from run-on of environment-

Three Rules Explain Transgenerational Small RNA Inheritance inC. elegans

“…Small RNA libraries. Small RNA libraries were processed and analyzed as recently described[24]. Normalization of the total number of reads in each sample, and the total number of reads which align to the different types of genomic features was generated based on the SizeFactor normalization provided by the DESeq2 package (the median ratio method).…”

“…1B ). In the past, RNAi experiments were traditionally performed by exposing populations of worms to RNAi followed by random sampling of worms in every generation[8,24,25]. Our experiments, in which we examined inheritance across lineages that originate in single mothers, reveal that the variability in the inheritance dynamics that is observed in population-based assays can be attributed to differences that begin in the RNAi-exposed mothers.…”

“…Exogenous introduction of double stranded RNA (dsRNA) triggers transgenerational silencing of germline genes [9]. Typically, heritable RNAi is maintained for ~3-5 generations (the so-called “bottleneck” to RNAi inheritance [9]), unless it is re-set earlier by stress [24]. While this is the usual duration of heritable responses at the population level, some individuals continue to silence genes for multiple generations, and others rapidly lose the inherited effects.…”

“…Survival during long periods of starvation requires HSF-1 [39]. In the absence of food, worms arrest their development at the first larval stage; Starvation alters the transgenerational pool of heritable small RNAs [6,24], and leads to multiple phenotypic changes in the progeny, such as increased lifespan [6], reduced fecundity and increased heat resistance [40]. Interestingly, isogenic worms produce different transgenerational responses following starvation [40].…”

Nongenetic inheritance and multigenerational plasticity in the nematode C. elegans

“…Increased stress resistance following selection for starvation resistance therefore represents a potential example of epigenetic adaptation by selection on pre-existing variation, though induction of nongenetic variation may also occur (adaptive multigenerational plasticity). Heritable changes in small RNA expression have been reported following L1 starvation ( Rechavi et al, 2014 ; Houri-Ze’evi et al, 2019 ), suggesting a source of epigenetic variation affecting phenotype. However, the extent of selection in these studies is unclear, and it is unknown if or how small RNAs mediate consequential effects on resistance to starvation or heat.…”