Understanding the regulation and impact of transposable elements in Vertebrate health and disease

项目总结 我的实验室的首要目标是了解未被充分研究的基因组调控机制，以及如何 它们影响终生脊椎动物的健康和疾病。在多细胞生物体中，不同类型的细胞 以特定的基因组调控模式为特征，对这些模式的精确控制不仅是关键 对于发育，也对成人的细胞/组织动态平衡。事实上，在基因组调控中失去精细控制 与疾病(如癌症、神经退行性变)和年龄相关的功能衰退有关。一个有趣的故事 而研究不足的基因组元件家族存在于休眠的遗传寄生虫(例如，转座子，也称为 “跳跃基因”)。尽管转座子可以代表一些真核生物基因组的80%，但它们仍然 严重不足的研究，因为他们在历史上被认为不重要(即“垃圾DNA”)，和他们的高 拷贝数量和重复性构成了独特的技术挑战。与它们在以下方面的潜在影响一致 无论是健康还是疾病，细胞抑制转座子活性的能力随着疾病和年龄的增长而被破坏。 此外，越来越多的证据表明，生物学和基因组调控的许多方面不同于 男性和女性，包括新出现的数据表明转座子活动中潜在的性别二型性。 然而，在健康的身体组织和健康的身体组织中，转座元件在整个生命过程中是如何受到调节的 在生物性别之间，以及它们如何影响脊椎动物健康，在很大程度上仍然是未知的。因此，我们 建议破译健康体细胞(包括男性和女性细胞)中转座子是如何受到控制的， 以及失去这种控制会如何影响脊椎动物的健康和疾病。为了探讨这个问题，我的团队 将使用一种独特的组合--“组学”方法、机器学习和动物实验验证 模特们。我们使用两种脊椎动物模型来比较它们各自的优势：实验室小鼠(例如，强大的 遗传学、有效抗体等)还有非洲绿松石鱼，一种自然短命的模式生物。 (例如，世代时间/寿命短、菌株多样性、成本效益等)。首先，我们将 破译性别-转座子活性的二态调节，确定性腺激素与性别的影响- 染色体上的这种调节。第二，我们将使用功能基因组学来确定新的调控因子 体细胞中转座子的活性。最后，我们将评估转座子控制对关键体细胞的影响 组织和性别对脊椎动物终身健康的影响使用天然的短暂的非洲绿松石龙鱼作为 一个模特。最终，了解转座子在健康细胞中的精细控制将有助于制定策略 通过让我们保持年轻和健康的基因组调节，防止它们在疾病中的错误调节 风景画。 1

Project summary The overarching goal of my lab is to understand understudied mechanisms of genomic regulation, and how they influence lifelong Vertebrate health and disease. In multi-cellular organisms, diverse cell types are characterized by specific genomic regulation patterns, and the precise control of these patterns is key not only for development, but also for cell/tissue homeostasis in adults. Indeed, loss of fine control in genomic regulation has been linked to disease (e.g. cancer, neurodegeneration) and age-related functional decline. An interesting and understudied family of genomic elements lies in dormant genetic parasites (e.g. transposons, also called “jumping genes”). Although transposons can represent up to 80% of some eukaryotic genomes, they remain critically understudied, since they were historically dismissed as unimportant (i.e. “junk DNA”), and their high copy numbers and repetitive nature pose unique technical challenges. Consistent with their potential impact in health and disease, the ability of cells to suppress transposon activity is disrupted with disease and with aging. In addition, accumulating evidence suggests that many aspects of biology and genomic regulation differ between males and females, including emerging data suggesting potential sex-dimorphism in transposon activity. However, how transposable elements are regulated throughout life in healthy somatic tissues and across biological sexes, and how they influence vertebrate health, remains largely unknown. Thus, we propose to decipher how transposons are controlled in healthy somatic cells (including in male vs. female cells), and how loss of that control could influence Vertebrate health and disease. To explore this question, my group will use a unique combination of ‘omics’ approaches, machine-learning, and experimental validation in animal models. We use two vertebrate models for their respective strengths: the laboratory mouse (e.g. powerful genetics, validated antibodies, etc.) and the African turquoise killifish, a naturally short-lived model organism I have helped develop (e.g. short generation time/lifespan, strain diversity, cost-effectiveness, etc.). First, we will decipher sex-dimorphic regulation of transposon activity, determining the impact of gonadal hormones vs. sex- chromosomes on such regulation. Second, we will use functional genomics to identify new regulators of transposon activity in somatic cells. Finally, we will evaluate the impact of transposon control in key somatic tissues and across sexes on lifelong vertebrate health using the naturally short-lived African turquoise killifish as a model. Ultimately, understanding the fine control of transposon in healthy cells will help devise strategies to prevent their misregulation in disease, by allowing us to maintain youthful and healthy genomic regulation landscapes. 1