Cracking the Code of Transgenerational Inheritance of Behavior

项目总结 已经在蠕虫、苍蝇和小鼠身上观察到跨代表观遗传(TEI)，并提出了 在人类中(例如，荷兰饥饿冬季)，但潜在的和调控的分子机制在很大程度上 未知。同样，我们还不知道普遍存在的跨王国信号是如何在病原体和 主持人才是。因此，在模型系统中研究这些机制是至关重要的。 我们最近发现，既吃细菌又被细菌感染的线虫可以 调查它的环境，检测并学会避免病原体，然后将这些信息传递给四个 它的后代的后代(Moore等人，Cell 2019)；我们认为这是一种新生形式的适应性免疫。 保守的分子过程(RNA干扰、COMPASS组蛋白修饰、piRNA) 需要几种组织(肠道、生殖线和神经元)来改变对假单胞菌的行为 铜绿假单胞菌(PA14)。蠕虫“读取”细菌的小RNA信号，将这一信息解释为未来的预测器 感染，并通过下调具有互补性的神经元基因来传递信息以改变行为 序列(Kaletsky，et al.BioRxiv 2020；Kaletsky等人。自然，在印刷中)。 SRNA信号是如何从胚系传递到神经元的？我们发现， Ty3/Gypsy逆转录转座子Cer1是习得的致病回避、TEI和PA14生存所必需的。这 范式转变：传统观点认为反转录转座子是有害的，而piRNAs 对抑制这些基因组寄生虫至关重要。相反，我们的结果表明Cer1可能被选为 对抗线虫环境中最丰富的病原体。我们假设Cer1形成囊泡- 比如携带sRNA到神经元的颗粒。拟议中的实验将表征生殖系到- 神经元信号，决定进化守恒的机制，并决定如何 跨代的“时钟”设置好了。因为我们已经观察到的分子成分是保守的， 我们的结果将确定其他动物对TEI的候选分子需求。

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.