Bacterial small RNAs and host epigenetic effectors of a transgenerational memory of pathogens inC. elegans

Abstract

The inheritance of memories is adaptive for survival. Microbes interact with all organisms challenging their immunity and triggering behavioral adaptations. Some of these behaviors induced by bacteria can be inherited although the mechanisms of action are largely unexplored. In this work, we use C. elegans and its bacteria to study the transgenerational RNA dynamics of an interspecies crosstalk leading to a heritable behavior. Heritable responses to bacterial pathogens in the nematode include avoidance and pathogen-induced diapause (PIDF), a state of suspended animation to evade the pathogen threat. We identify a small RNA RsmY, involved in quorum sensing from P. aeruginosa as required for initiation of PIDF. Histone methyltransferase SET-18/SMYD3 is also needed for PIDF initiation in C. elegans. In contrast, SET-25/EHMT2 is necessary for the maintenance of the memory of pathogen exposure in the transgenerational lineage. This work can be a starting point to understanding microbiome-induced inheritance of acquired traits.

The Heritability of Behaviors Associated With the Host Gut Microbiota

“…toxicants presence, high fat diet, osmotic and thermal stress, caloric restriction, among others) is transmitted from parents to subsequent generations (152,153). In C. elegans small RNAs produced by the host (4,7,36,83,84,(154)(155)(156) and bacteria (85,86,157) are primary effectors for driving environmentally induced heritable behaviors. However, how environmental changes are sensed and then transmitted to the progeny breaching the germline to soma barrier is still not fully understood.…”

“…In C. elegans, neuron-specific synthesis of sRNAs regulates the amplification of endogenous siRNAs in germ cells, thus changing germline gene expression for multiple generations (83,84). This mechanism opens the possibility that an olfactory stimulus elicited by bacteria changes the repertoire of endogenous neuronal sRNAs, which can later promote epigenetic changes in germ cells that will affect the offspring's behavior and fitness.…”

Interspecies RNA Interactome of Pathogen and Host in a Heritable Defensive Strategy

“…Relevance of RNA-RNA Communication in Behavior and Physiology Bacterial RNAs are capable of triggering behavioral decisions in their nematode host (Kaletsky et al, 2020;Legüe et al, 2021). How do RNAs from the two species interact with each other in the context of a holobiont?…”

“…In this scenario, interspecies sequences would interact with nearly perfect complementarity. To prove this, we compared public genomic data and transcriptomic data generated in a previous work (Legüe et al, 2021) from bacteria grown on standard LB broth (naïve bacteria) and for six generations in the transgenerational paradigm shown in Figure 1A. We searched for sRNAs from naïve P. aeruginosa PAO1 that matched regions of the C. elegans genome (Figure 1B).…”

“…For instance, Escherichia coli non-coding RNAs (ncRNAs) OxyS and DsrA affect chemotaxis and longevity in Caenorhabditis elegans by downregulating che-2 ( Liu et al, 2012 ). Salmonella enterica microRNA-like RNA fragment Sal-1 targets host-inducible nitric oxide synthase ( Zhao et al, 2017 ); Pseudomonas aeruginosa PA14 methionine-transfer RNAs (tRNA) fragment from outer membrane vesicles (OMVs) induces IL-8 secretion in human epithelial cells ( Koeppen et al, 2016 ); ncRNA p11 induces intergenerational learned avoidance in C. elegans by targeting maco-1 ( Kaletsky et al, 2020 ); and P. aeruginosa PAO1 RsmY triggers transgenerational diapause ( Legüe et al, 2021 ).…”