Abstract
Transgenerational inheritance of small RNAs challenges basic concepts of heredity. In Caenorhabditis 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.
Highlights
Different human diseases, such as several imprinting-associated syndromes (Angelman syndrome, Prader-Willi syndrome, and Beckwith-Wiedemann syndrome), arise due to the inheritance of parental information that is not encoded in the DNA sequence (Tucci et al, 2019)
Stress resets endogenously derived heritable small RNA silencing within the same generation in the second and third sets of assays of small RNA inheritance, we examined if stress can reset heritable silencing that is triggered by endogenous small interfering RNAs or PIWI-interacting small RNAs
We found that MAP Kinase (MAPK) genes, and the skn-1 gene are required for resetting of RNA interference (RNAi) inheritance in response to stress (Figure 5B and C, and Figure 5—figure supplements 1 and 2), in addition to their effects on RNAi inheritance even in the absence of stress, as described above. skn-1/ Nrf2 encodes a transcription factor which is regulated by p38 MAPK-dependent phosphorylation (Inoue et al, 2005)
Summary
Different human diseases, such as several imprinting-associated syndromes (Angelman syndrome, Prader-Willi syndrome, and Beckwith-Wiedemann syndrome), arise due to the inheritance of parental information that is not encoded in the DNA sequence (Tucci et al, 2019). Small RNA inheritance factors, which are required for the regulation of heritable responses, have been identified (Ashe et al, 2012; Buckley et al, 2012; de Albuquerque et al, 2015; Houri-Ze’evi et al, 2016; Lev et al, 2019b; Lev et al, 2017; Shirayama et al, 2012; Wan et al, 2018; Xu et al, 2018), and specific worm Argonaute proteins (HRDE-1, CSR-1, WAGO-4, WAGO-1) were found to physically carry small RNAs in the germline and across generations (Ashe et al, 2012; Claycomb et al, 2009; Shirayama et al, 2012; Wedeles et al, 2013; Xu et al, 2018). The amplification reaction outcompetes the dilution of the heritable small RNA molecules in every generation and enables the transgenerational transmission of small RNAs (Rechavi et al, 2011).
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