Epigenetic regulation of extreme longevity differences in ant castes

蚂蚁种姓极端长寿差异的表观遗传调控

• 批准号: 10608683
• 负责人: SHELLEY L BERGER
• 金额: $ 45.94万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608683
• 关键词: Age; Aging; Animal Model; Ants; Behavior; Binding; Biological Models; Castes; Chromatin; Complex; Ectopic Expression; Epigenetic Process; Etiology; Excision; Exhibits; Family; Female; Food; Foundations; Funding; Genetic; Genetic Transcription; Genome; Genomics; Goals; HSF1; Heart; Heat Stress Disorders; Heat shock factor; Heat-Shock Response; Heat-Shock Transcription Factor 2; Histone Acetylation; Individual; Insecta; Investigation; Knowledge; Lead; Life; Link; Longevity; Mammals; Messenger RNA; MicroRNAs; Minor; Modeling; Pathway interactions; Physiological; Proteins; Proteomics; Regulation; Reproduction; Research; Role; Social Behavior; Soldier; Sterility; Stress; Testing; Translating; Up-Regulation; base; epigenetic regulation; epigenomics; histone methylation; human model; mortality; non-genetic; novel; protein structure; reproductive; transcription factor

ABSTRACT Ants exhibit highly evolved eusocial behaviors including stark division of labor among female castes, where the queen carries out all reproduction and worker castes forage for food and defend the colony. Interestingly, and of great relevance to aging research, sterile workers are shorter-lived, with variable lifespans between distinct castes. Reproductive queens are long-lived, with lifespans differing three to ten-fold between queen and worker. Remarkably, the genomes of the sterile and reproductive castes are nearly identical, and thus differences in lifespan and behavior arise from non-genetic mechanisms. We investigate two species of ants, each with advantages for study of mechanisms linking aging with complex social behavior. In Harpegnathos saltator, loss or removal of the queen leads to altered behavior in the workers, with antennal dueling and eventual ascendance of workers to reproductive status. From a longevity perspective, the induced reproductive caste exhibits four-fold longer lifespan, thus providing a simple experimental switch to uncover important causality underlying aging. In Camponotus floridanus, there are two distinct worker castes, forager and soldier, with the soldier exhibiting a two-fold longer lifespan than the forager. These behaviors are programmed early in life, but exhibit plasticity during aging. Intriguingly, these castes can be experimentally reprogrammed from soldier-to-forager, thus providing a second paradigm to study the relationship of behavior to aging. Our overall premise is that genomic, epigenomic, and proteomic regulation—all hallmark foundational causes of aging—are at the heart of caste-differentiated lifespan disparities and relationship to caste behavior. We thus propose to utilize ants to investigate the epigenetic and physiological basis of the dramatic lifespan differences between reproductive and distinct worker castes. In H. saltator we have evidence in the long-lived reproductive caste for two mechanisms extending lifepan. First, we detect increased expression of a unique HSF (Heat Shock Factor) providing proteomic protection and longer lifespan via upregulation of the Heat Shock Response transcriptional pathway. Second, we find increased expression of a unique Ago2 (Arogonaut) that binds miRNAs that specifically target for destruction certain mRNAs that lower lifespan in short-lived workers. In C. floridanus we find that distinct chromatin-based epigenetic mechanisms are central to foraging, which is an age-linked behavior, and we can manipulate these pathways to reprogram soldier caste to forage. In the proposed research we will investigate these causal mechanisms, and then manipulate lifespan with a combination of genetic and epigenetic approaches to promote these mechanisms. The ant model system provides an exceptional opportunity to integrate social behavior with aging, and to uncover key epigenetic processes underlying universal aging pathways. Results from the research will provide fundamental knowledge about control of lifespan that can be translated to more sophisticated mammals.

摘要 蚂蚁表现出高度进化的社会行为，包括女性种姓之间的赤裸裸的劳动分工，其中 女王执行所有繁衍和工人种姓觅食和保卫殖民地。有趣的是，还有 与老龄化研究密切相关的是，不育工人的寿命较短，不同的人的寿命不同 种姓。繁殖女王的寿命很长，它们的寿命相差三到十倍。 工人。值得注意的是，不育种姓和生殖种姓的基因组几乎完全相同，因此 寿命和行为的差异是由非遗传机制引起的。我们调查了两种蚂蚁， 它们在研究衰老与复杂的社会行为之间的联系机制方面各有优势。在哈佩格纳托斯 跳跃，失去或移走蚁后会导致工蚁行为的改变，包括触角决斗和 工人最终会上升到生殖状态。从长寿的角度来看，诱导生殖 种姓的寿命延长了四倍，因此提供了一个简单的实验开关来揭示重要的 衰老背后的因果关系。在Camponotus floridanus中，有两个截然不同的工人阶级，即Forager和 士兵，士兵的寿命是觅食者的两倍。这些行为是被编程的 在生命早期，但在衰老过程中表现出可塑性。有趣的是，这些种姓可以试验性地重新编程 从士兵到觅食者，从而为研究行为与衰老的关系提供了第二个范式。我们的 总体前提是基因组、表观基因组和蛋白质组调控-所有这些都是 老龄化--是种姓差别寿命差异的核心，也是种姓行为的关系。 因此，我们建议利用蚂蚁来研究戏剧的表观遗传学和生理基础。 生殖工种和不同工种之间的寿命差异。在H.Saltator中，我们有证据表明 长寿的生殖种姓有两种延长寿命的机制。首先，我们检测到一个基因的表达增加 独特的HSF(热休克因子)通过上调 热休克反应转录途径。第二，我们发现一种独特的Ago2的表达增加 (宇航员)，它结合了专门针对破坏某些降低寿命的mRNA的miRNA 短命的工人。在华丽隐杆藻中，我们发现不同的基于染色质的表观遗传机制是 觅食，这是一种与年龄相关的行为，我们可以操纵这些路径来重新编程士兵的种姓 去觅食。在拟议的研究中，我们将研究这些因果机制，然后操纵寿命 通过结合遗传和表观遗传方法来促进这些机制。蚂蚁模型 系统提供了一个将社会行为与老龄化相结合的绝佳机会，并揭示了关键 普遍衰老途径背后的表观遗传过程。这项研究的结果将为 关于控制寿命的知识，可以转化为更复杂的哺乳动物。