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，包括女性种姓之间严格的劳动分工，其中 女王负责所有繁殖工作，工蚁则寻找食物并保卫殖民地。有趣的是，并且 与衰老研究密切相关的是，不育工蜂的寿命很短，而繁殖蜂王的寿命却很短。 寿命长，蜂王和工蜂的寿命相差三到十倍。值得注意的是，基因组 这些不育种姓和生殖种姓几乎相同，因此寿命（LS）和行为也存在差异 可能是表观遗传调控的结果。此外，在 Harpegnathos saltator 物种中，损失或去除 蚁后会导致工蚁的行为发生改变，通过触角决斗并最终占据典型的地位。 一两个工人进入生殖“玩家门”，或伪女王。从长寿的角度来看， 玩家门表现出更长的 LS，因此行为和寿命似乎都是由表观遗传决定的 在此切换期间。此外，老年工人重新编程进入生殖玩家门的效率要低得多 状态。我们的总体前提是表观遗传调控是种姓差异寿命的核心 一旦我们了解了表观遗传调控的基础，我们就可以通过以下方式操纵寿命 在这个相对简单但社会复杂的有机体中进行表观遗传治疗和遗传学。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 H. salator ant 来研究其表观遗传和生理基础。 生殖种姓和工人种姓之间存在显着的 LS 差异。我们将进行转录组学、蛋白质组学、 以及同龄工蚁和蚁后、年轻蚁后和年老蚁后的表观基因组分析， 探索寿命可塑性的基础。我们假设已知的和新颖的机制都是 皇后的 LS 延长，这与工蜂 LS 表现出巨大的差异。此外，我们还将揭开 这是将老年工人低效重新编程为生殖玩家门的基础。我们最近发布的 证据（Science，2016）支持这样的观点：表观遗传增强了蚂蚁的行为可塑性 成年早期的机制，并且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然未知。我们关于染色质标记的初步数据 表明玩家门女王中靠近活性基因的调控位点具有激活组蛋白 H3K27 乙酰化作用 工人中的这些相同位点被标记为抑制性 H3K27 甲基化。有趣的是，这些被压抑的 工蚁中的基因座似乎“准备好”被 H4K16 乙酰化激活。我们假设在年轻人中 工蚁的关键基因座在表观遗传上准备被激活，并且这种平衡会随着工蚁的发生而退化 年龄，导致对生殖状态的低效重编程。在拟议的研究中，我们将测试这一点 使用表观遗传疗法和遗传学的建议。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.