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

了解转座因子对脊椎动物健康和疾病的调节和影响

• 批准号: 10650781
• 负责人: Berenice Anath Benayoun
• 金额: $ 41.25万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-20 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650781
• 关键词: Adult; African; Aging; Animal Model; Antibodies; Big Data; Biology; Cells; Cues; DNA Transposable Elements; Data; Development; Disease; Elements; Family; Female; Generations; Genetic; Genome; Genomics; Goals; Gonadal Hormones; Health; Homeostasis; Jumping Genes; Junk DNA; Killifishes; Laboratory mice; Life; Link; Longevity; Machine Learning; Malignant Neoplasms; Mobile Genetic Elements; Modeling; Mus; Nature; Nerve Degeneration; Organism; Parasites; Pattern; Physiology; Regulation; Research; Sex Chromosomes; Somatic Cell; Time; Tissues; Validation; age related; biological sex; cell type; cost effectiveness; functional decline; functional genomics; male; model organism; prevent; programs; response; sex; sexual dimorphism

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

项目概要 我实验室的首要目标是了解尚未研究的基因组调控机制，以及如何 它们影响脊椎动物的终生健康和疾病。在多细胞生物中，不同的细胞类型 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 用于发育，也用于成人的细胞/组织稳态。事实上，基因组调控失去精细控制 与疾病（例如癌症、神经退行性疾病）和与年龄相关的功能衰退有关。一个有趣的 尚未研究的基因组元件家族存在于休眠的遗传寄生虫中（例如转座子，也称为 “跳跃基因”）。尽管转座子可以代表某些真核生物基因组的 80%，但它们仍然 由于它们在历史上被视为不重要（即“垃圾 DNA”）而被忽视，因此对其进行了严格的研究，并且它们的高 拷贝数和重复性带来了独特的技术挑战。与其潜在影响一致 健康和疾病中，细胞抑制转座子活性的能力会因疾病和衰老而受到破坏。 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物种之间存在差异。 男性和女性，包括表明转座子活动中潜在性别二态性的新数据。 然而，转座因子在健康体细胞组织的整个生命过程中是如何调节的？ 跨生物性别，以及它们如何影响脊椎动物的健康，在很大程度上仍然未知。因此，我们 提议破译转座子在健康体细胞（包括男性与女性细胞）中是如何控制的， 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，我的小组 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。我们使用两种脊椎动物模型来发挥各自的优势：实验室小鼠（例如强大的 遗传学、经过验证的抗体等）和非洲绿松石鳉鱼，一种自然寿命较短的模式生物 I 有助于发展（例如，世代时间/寿命短、菌株多样性、成本效益等）。首先，我们将 破译转座子活性的性别二态性调节，确定性腺激素与性别的影响 染色体对这种调节。其次，我们将利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对关键体细胞的影响 使用自然寿命较短的非洲绿松石鳉鱼作为组织和跨性别对脊椎动物终生健康的影响 一个模型。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控来防止它们在疾病中的错误调控 风景。 1