Cracking the Code of Transgenerational Inheritance of Behavior

破解行为跨代遗传的密码

• 批准号: 10493431
• 负责人: Coleen Tara Murphy
• 金额: $ 111.68万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10493431
• 关键词: Affect; Animals; Bacteria; Bacterial RNA; Behavior; Biological Models; Caenorhabditis elegans; Cells; Code; Eating; Environment; Evolution; Future; Generations; Genes; Genomics; Gypsies; Health; Human; Hunger; Infection; Intestines; Learning; Logic; Longevity; Metabolism; Molecular; Mus; Nature; Nematoda; Neurons; Parasites; Pathogenicity; Play; Process; Pseudomonas aeruginosa; RNA Interference; Retrotransposon; Role; Signal Transduction; Small RNA; Surveys; System; Tissues; Vesicle; adaptive immunity; behavior influence; experience; experimental study; fight against; fly; grandparent; histone modification; particle; pathogen; piRNA; response; transgenerational epigenetic inheritance

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.

项目摘要 已经在蠕虫、苍蝇和小鼠中观察到了跨代表观遗传（TEI），并提出了 在人类中（例如，荷兰饥饿冬季），但潜在的和调节的分子机制在很大程度上 未知类似地，我们还不了解病原体之间无处不在的跨界信号传导， 霍斯群岛因此，在模型系统中研究这些机制至关重要。 我们最近发现线虫C.线虫既吃东西又被细菌感染， 调查它的环境，发现并学会避免病原体，然后将这些信息传递给四个 其后代的世代（摩尔等人，Cell 2019）;我们认为这是一种新生形式的适应性免疫。 在整个基因组中，高度保守的分子过程（RNA干扰、COMPASS组蛋白修饰、piRNA） 需要几种组织（肠、生殖细胞和神经元）来改变行为以响应假单胞菌 铜绿假单胞菌（PA 14）。蠕虫“阅读”小RNA细菌信号，将此信息解释为未来的预测 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等人BioRxiv 2020; Kaletsky等人Nature，出版中）。 sRNA信号是如何从生殖细胞传递到神经元的？我们发现 Ty 3/Gypsy反转录转座子Cer 1是PA 14上学习致病性避免、TEI和存活所必需的。这 是范式转变：传统观点认为反转录转座子是有害的，piRNA 对抑制这些基因组寄生虫至关重要相反，我们的研究结果表明，Cer 1可能被选择为 对抗C. elegans环境。我们假设Cer 1形成囊泡- 就像将sRNA携带到神经元的颗粒一样。拟议的实验将表征生殖系到 神经元信号，确定机制的进化保守性，并确定 跨代的“时钟”已定。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TEI的候选分子要求。