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，不育的工蜂寿命很短，而繁殖的蜂王寿命很短。 寿命长，蚁后和工蚁的寿命相差三到十倍。值得注意的是， 这些不育和生殖种姓几乎是相同的，因此在寿命（LS）和行为上存在差异 很可能是由表观遗传调控引起的。此外，在物种Harpegnathos saltator中， 蚁后会导致工蜂的行为改变，触角决斗，并最终导致典型的 一到两个工蜂变成繁殖的“gamergate”，或者说伪女王。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，年龄较大的工人重新编程到生殖gamergate效率低得多 status.我们的总体前提是，表观遗传调节是这种种姓分化寿命的核心 一旦我们理解了表观遗传调控的基础，我们就可以操纵寿命， 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 提供了可以在更复杂的哺乳动物中进行研究的基础知识。 我们建议使用H。跳跃蚂蚁调查表观遗传和生理基础的 生育种姓和工人种姓之间的巨大的一次生活费用差异。我们将进行转录组，蛋白质组， 和表观基因组分析相同实足年龄的工蚁和蚁后，以及年轻和年老的蚁后， 探索生命可塑性的基础。我们假设已知的和新的机制都是 延长了皇后的LS，这表明工人LS如此显着的差异。此外，我们还将揭开 这是老年工人重新编程为生殖性游戏者的效率低下的基础。我们最近出版的 证据（科学，2016）支持这样的观点，即蚂蚁的行为可塑性是由表观遗传增强的。 在年轻的成年期，这种可塑性随着年龄的增长而消失;然而， 这一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 显示了在携带激活组蛋白H3 K27乙酰化Gamergate Queens中靠近活性基因的调节位点 在工蜂中，这些相同的基因座标记有抑制性H3 K27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H4 K16乙酰化激活。我们假设在年轻人中 工蜂的关键基因座在表观遗传学上处于被激活的状态， 年龄，导致无效的重新编程到生殖状态。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 有机会将社会行为与衰老结合起来，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.