Epigenetic regulation of extreme longevity differences in ant castes

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，不育工蚁的寿命很短，而生殖女王的寿命却很短 长寿，蜂王和工蚁的寿命相差三到十倍。值得注意的是，它们的基因组 这些不育种姓和生殖种姓几乎完全相同，因此在寿命(LS)和行为上也存在差异 很可能是表观遗传调控的结果。此外，在Harpegnathos saltator物种中，丧失或移除 蜂王导致工蚁行为的改变，触角决斗和最终的优势典型 一到两只工蜂变成繁殖的“配偶门”，或伪女王。从长寿的角度来看， Gamergate表现出更长的LS，因此似乎行为和寿命都是由表观遗传决定的 在这个转换过程中。此外，年长的工作者将程序重新编程为生殖配偶门的效率要低得多 状态。我们的总体前提是，表观遗传调控是这种种姓分化寿命的核心 差异，一旦我们理解了表观遗传调控的基础，我们就可以通过 表观遗传疗法和遗传学在这个相对简单但社会复杂的有机体中。这些结果将 提供可以在更复杂的哺乳动物中进行研究的基础知识。 我们建议利用跳跃蚂蚁来研究其表观遗传学和生理基础。 生殖种姓和工人种姓之间的显著差异。我们将进行转录组学，蛋白质组学， 以及相同年龄段的工蚁和蜂王，以及年轻和年老的蜂王的表观基因组图谱， 探讨寿命可塑性的基础。我们假设已知的和新的机制都是 在蜂王身上加长LS，显示出与工蜂LS如此显著的差异。此外，我们还将揭开 这是将年长的工蚁重新编程为生殖配子门效率低下的基础。我们最近出版的 证据(《科学》2016)支持这样的观点，即表观遗传增强了蚂蚁的行为可塑性 机制，这种可塑性随着年龄的增长而丧失；然而，分子 这种现象背后的机制仍不清楚。我们关于染色质标记的初步数据 显示配子门女王活性基因附近的调控基因具有激活组蛋白H3K27乙酰化的作用 而在工人身上，这些相同的基因座被标记为抑制性H3K27甲基化。有趣的是，这些被压抑的 工蚁体内的基因座似乎已经准备好通过H4K16乙酰化来激活。我们假设在杨格 工人的关键基因座在表观遗传上准备被激活，而这种平衡随着工人的降级而退化 年龄，导致重新编程到生殖状态的效率低下。在拟议的研究中，我们将测试这一点 建议使用表观遗传疗法和遗传学。蚂蚁模型系统提供了一个特殊的 将社会行为与衰老相结合的机会，并揭示潜在的关键表观遗传过程 普遍的衰老途径。

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, the sterile workers are short-lived, while the reproductive queens are long-lived, with lifespans differing three to ten-fold between queen and worker. Remarkably, the genomes of these sterile and reproductive castes are nearly identical, and thus differences in lifespan (LS) and behavior likely result from epigenetic regulation. Furthermore, in the species Harpegnathos saltator, loss or removal of the queen leads to altered behavior in the workers, with antennal dueling and eventual ascendance of typically one or two workers into reproductive “gamergate”, or pseudo-queen. From a longevity perspective, the gamergate exhibits longer LS and thus it appears that both behavior and lifespan are epigenetically determined during this switch. In addition, older workers reprogram much less efficiently into reproductive gamergate status. Our overall premise is that epigenetic regulation is at the heart of this caste-differentiated life span disparity, and that once we understand the basis of the epigenetic regulation, we can manipulate lifespan with epigenetic therapeutics and genetics in this relatively simple but socially complex organism. These results will provide fundamental knowledge that can be investigated in more sophisticated mammals. We propose to utilize H. saltator ants to investigate the epigenetic and physiological basis of the dramatic LS differences between reproductive and worker castes. We will carry out transcriptomic, proteomic, and epigenomic profiling of workers and queens of the same chronological age, and of young and old queens, to explore the basis of the plasticity in lifespan. We hypothesize that both known and novel mechanisms are lengthening LS in queens, which show such dramatic difference from worker LS. In addition, we will uncover the basis of the inefficient reprogramming of older workers into reproductive gamergates. Our recent published evidence (Science, 2016) supports the view that behavioral plasticity in ants is enhanced by epigenetic mechanisms during young adulthood, and that this plasticity is lost with age; however, the molecular mechanisms underlying this phenomenon remain unknown. Our preliminary data regarding chromatin marking show that regulatory loci near to active genes in gamergate queens bear activating histone H3K27 acetylation and these same loci in worker are marked with repressive H3K27 methylation. Intriguingly, these repressed loci in worker ants appear to be “poised” for activation with H4K16 acetylation. We hypothesize that in young workers key loci are epigenetically poised to become activated and this poising becomes degraded as workers age, leading to inefficient reprogramming to reproductive status. In the proposed research we will test this proposal using epigenetic therapeutics and genetics. The ant model system provides an exceptional opportunity to integrate social behavior with aging, and to uncover key epigenetic processes underlying universal aging pathways.