Regulation, function, and impact of developmental retrotransposon activation

摘要 逆转录转座子是几乎所有动物细胞中最丰富的遗传元件，占所有动物细胞的38%。 人类基因组它们的激活固有地导致DNA损伤和突变，并且这种活动越来越多地被用于治疗癌症。 被认为会导致许多人类疾病。尽管它们的数量和对宿主的基本影响 尽管逆转录转座子的研究在生理学和病理学上是一个未充分探索的生物医学研究领域。 使用我的团队开发的新工具和技术，从长远来看，我们的目标是了解 反转录转座子的活动是发育调节的，它们的功能和影响是什么？ 在生理和病理条件下对宿主的发育激活。 我们的早期进展揭示了发育中的反转录转座子激活、宿主 免疫力和抗病毒反应。这些结果引出了我们的中心假设： 逆转录转座子激活启动免疫系统，给予宿主长期的保护， 病原体感染针对这一假设，我们发现吉普赛人的反转录转座子选择性地 在果蝇的变态过程中在新生组织中变得活跃。我们还发现 吉普赛激活触发抗菌肽（AMP）的产生，抗菌肽是先天免疫的效应物。 令人兴奋的是，我们进一步了解到，在变态过程中抑制吉普赛激活会导致苍蝇屈服于 成年后的病毒感染在这些强有力的初步数据的指导下，我们建议追求三个具体的 目的是表征这种Gypsy激活机制，并揭示Gypsy信号AMP生产和 最终促进抗病毒反应：（1）表征Gypsy活性在动物体内是如何调节的。 发展(2)阐明吉普赛激活启动宿主先天免疫的分子机制。 (3)定义吉普赛激活对抗击病原体的长期影响。 总的来说，我们提出的研究将通过确定控制癌症的新机制来广泛影响该领域。 逆转录转座子和表征逆转录转座子对宿主免疫的影响。鉴于激活 逆转录转座子的表达可能有助于神经退行性疾病的炎症， 免疫原性的癌细胞，我们的研究结果将有可能提供新的视角，利用它们来治疗 相关疾病。

ABSTRACT Retrotransposons are the most abundant genetic elements in almost all animal cells, making up 38% of the human genome. Their activation inherently leads to DNA damage and mutations, and this activity is increasingly appreciated to cause numerous human diseases. Despite their abundance and fundamental impacts on host physiology and pathology, the study of retrotransposons remains an underexplored area of biomedical research. Using new tools and technologies developed by my team, in the long-term, we aim to understand how retrotransposon activity is developmentally regulated, and what are the function and impact of their developmental activation to the hosts under physiological and pathological conditions. Our early progress revealed an unexpected convergence among developmental retrotransposon activation, host immunity, and antiviral response. These results lead to our central hypothesis that developmentally programed retrotransposon activation primes the immune system to grant the hosts a long-term protection against future pathogen infections. Toward this hypothesis, we have discovered that Gypsy retrotransposon selectively becomes active in the newly regenerating tissues during Drosophila metamorphosis. We have also found that Gypsy activation triggers the production of antimicrobial peptides (AMPs), the effectors of innate immunity. Excitingly, we further learned that suppressing Gypsy activation during metamorphosis leads flies to succumb to viral infection at adulthood. Guided by these strong preliminary data, we propose to pursue three Specific Aims to characterize this Gypsy activation mechanism and to uncover how Gypsy signals AMP production and ultimately promotes an antiviral response: (1) Characterize how Gypsy activity is regulated during animal development. (2) Elucidate the molecular mechanisms by which Gypsy activation primes host innate immunity. (3) Define the long-term impact of Gypsy activation on combating pathogens. Collectively, our proposed research will broadly impact the field by identifying new mechanisms that control retrotransposons and characterizing the influence of retrotransposon on host immunity. Given that the activation of retrotransposon likely contributes to inflammation in neurodegenerative disease and increases immunogenicity of cancer cells, our findings will potentially provide new perspectives to harness them for treating related diseases.