Cracking the Code of Transgenerational Inheritance of Behavior

PROJECT SUMMARY Transgenerational epigenetic inheritance (TEI) has been observed in worms, flies, and mice, and proposed in humans (e.g., Dutch Hunger Winter), but the underlying and regulatory molecular mechanisms are largely unknown. Similarly, we do not yet understand how ubiquitous trans-kingdom signaling between pathogens and

hosts is. Therefore, it is critical to study these mechanisms in model systems. We recently discovered that the nematode C. elegans, which both eats and is infected by bacteria, can survey its environment, detect and learn to avoid pathogens, and then pass this information on to four generations of its progeny (Moore, et al., Cell 2019); we propose that this is a nascent form of adaptive immunity.

Well-conserved molecular processes (RNA interference, COMPASS histone modification, piRNAs) across several tissues (intestine, germline, and neurons) are required to alter behavior in response to Pseudomonas aeruginosa (PA14). Worms "read" small RNA bacterial signals, interpret this information as a predictor of future

infection, and transmit the information to alter behavior by downregulating a neuronal gene with complementary sequence (Kaletsky, et al. BioRxiv 2020; Kaletsky et al. Nature, in press). How is the sRNA signal conveyed from the germline to neurons? We found that the Ty3/Gypsy retrotransposon Cer1 is required for learned pathogenic avoidance, TEI, and survival on PA14. This

is paradigm shifting: conventional wisdom holds that retrotransposons are deleterious, and that piRNAs are critical to repress these genomic parasites. Our results instead suggest that Cer1 may have been selected to fight against the most abundant pathogens in C. elegans' environment. We hypothesize that Cer1 forms vesicle-

like particles that carry sRNAs to neurons. Proposed experiments will characterize the nature of the germline-to- neuron signal, determine the evolutionary conservation of the mechanism, and determine how the transgenerational “clock” is sett. Because the molecular components we have already observed are conserved,

our results will identify candidate molecular requirements for TEI in other animals.