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: 10708181
• 负责人: SHELLEY L BERGER
• 金额: $ 47.06万
• 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/10708181
• 关键词: Age; Aging; Animal Model; Ants; Behavior; Binding; Biological Models; Castes; Chromatin; Complex; Disparity; Ectopic Expression; Epigenetic Process; Etiology; Excision; Exhibits; Family; Female; Food; 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; 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; epigenetic regulation; epigenomics; histone methylation; human model; mortality; non-genetic; novel; programs; 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劳动分工， 蚁后负责所有的繁殖工作，工蜂负责觅食和保卫殖民地。有趣的是， 与衰老研究有很大关系的是，不育工人的寿命较短，不同年龄段的工人的寿命不同， 种姓繁殖女王是长寿的，女王和女王之间的寿命相差三到十倍。 worker.值得注意的是，不育和生殖种姓的基因组几乎是相同的， 寿命和行为的差异来自非遗传机制。我们研究了两种蚂蚁， 每一种都具有研究衰老与复杂社会行为联系机制的优势。在竖琴属 跳跃者，女王的损失或移除导致工蜂行为改变，触角决斗， 工人最终上升到生育地位。从长寿的角度来看， 种姓的寿命长四倍，从而提供了一个简单的实验开关，以揭示重要的 衰老背后的因果关系在佛罗里达弓背蚁中，有两个不同的工人种姓，觅食者和 士兵的寿命是觅食者的两倍。这些行为都是由 在生命的早期，但在衰老过程中表现出可塑性。有趣的是，这些种姓可以通过实验重新编程 从狩猎者到觅食者，从而提供了研究行为与衰老关系的第二种范式。我们 总的前提是基因组、表观基因组和蛋白质组调节--所有这些都是疾病的标志性基本原因 老龄化-是种姓差别化的寿命差距和与种姓行为的关系的核心。 因此，我们建议利用蚂蚁来调查戏剧性的表观遗传和生理基础。 生育种姓和不同工人种姓之间的寿命差异。In H.我们有证据表明， 长寿的生殖种姓为两种延长寿命的机制。首先，我们检测到一种 独特的HSF（热休克因子）通过上调蛋白质组保护和延长寿命， 热休克反应转录途径。第二，我们发现一种独特的Ago 2 （Arogonaut）结合特异性靶向破坏某些降低寿命的mRNA的miRNA， 短命的工人In C.我们发现，不同的染色质为基础的表观遗传机制是核心， 觅食，这是一种与年龄相关的行为，我们可以操纵这些途径来重新编程士兵种姓 去觅食在拟议的研究中，我们将调查这些因果机制，然后操纵寿命 结合遗传学和表观遗传学方法来促进这些机制。蚂蚁模型 系统提供了一个特殊的机会，将社会行为与老龄化相结合，并揭示关键的 表观遗传过程是普遍衰老途径的基础。研究结果将提供基本的 关于控制寿命的知识，可以转化为更复杂的哺乳动物。