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

项目摘要 我的实验室的首要目标是了解未充分研究的基因组调控机制，以及如何 它们会影响终生的脊椎动物健康和疾病。在多细胞生物体中， 其特征在于特定的基因组调控模式，这些模式的精确控制不仅是关键， 对于发育，而且对于成人中的细胞/组织稳态。事实上，基因组调控中的精细控制的丧失 与疾病（如癌症、神经变性）和年龄相关的功能衰退有关。一个有趣 基因组元件的未充分研究的家族存在于休眠的遗传寄生物（例如转座子，也称为 “跳跃基因”）。虽然转座子可以代表高达80%的一些真核生物基因组， 由于它们在历史上被认为是不重要的（即“垃圾DNA”）， 拷贝数和重复性质提出了独特的技术挑战。与其潜在影响一致， 在健康和疾病的过程中，细胞抑制转座子活性的能力随着疾病和衰老而被破坏。 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在不同的物种之间存在差异。 男性和女性，包括新出现的数据表明转座子活性的潜在性别二型性。 然而，转座因子在健康的体细胞组织中如何在整个生命过程中受到调节， 在生物性别之间，以及它们如何影响脊椎动物的健康，在很大程度上仍然是未知的。因此我们 建议破译转座子是如何在健康的体细胞（包括男性与女性细胞）中控制的， 以及失去控制会如何影响脊椎动物的健康和疾病。为了探索这个问题，我的团队 将使用“组学”方法，机器学习和动物实验验证的独特组合 模型我们使用了两种脊椎动物模型，它们各自的优势：实验室小鼠（例如，强大的 遗传学、经验证的抗体等）和非洲绿松石鳉，一种自然短命的模式生物， 有助于发展（例如，短世代时间/寿命、菌株多样性、成本效益等）。一是 破译转座子活性的性别二态调节，确定性腺激素与性别的影响- 染色体对这种调控。第二，我们将使用功能基因组学来识别新的调节因子， 体细胞中的转座子活性。最后，我们将评估转座子控制在关键体细胞中的影响， 组织和性别对脊椎动物终身健康的影响，使用自然寿命短的非洲绿松石鳉作为 模特最终，了解健康细胞中转座子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， 的风景. 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