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

基本信息

批准号：
10265910
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
项目类别：
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

项目摘要

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

项目摘要我实验室的总体目标是了解理解的基因组调节机制，以及如何它们会影响终生的脊椎动物健康和疾病。在多细胞生物中，各种细胞类型是以特定的基因组调节模式为特征，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。实际上，基因组调节中的良好控制丧失与疾病（例如癌症，神经变性）和年龄相关的功能下降有关。一个有趣的并理解基因组元素的家族在于休眠的遗传寄生虫（例如，也称为转座子 “跳跃基因”）。尽管转座子最多可以代表某些真核基因组的80％，但它们仍然保持批判性理解，因为历史上他们被认为不重要（即“垃圾DNA”），而他们的高复制数字和重复性构成独特的技术挑战。与它们在潜在的影响一致的健康和疾病，细胞抑制转座子活性的能力受到疾病和衰老的破坏。此外，积累的证据表明生物学和基因组调节的许多方面差异男性和女性，包括新兴数据表明转座子活性中潜在的性二态性。但是，在健康的体细胞组织中，如何调节可转座的元素和在整个生物学性别以及它们如何影响脊椎动物健康状况的情况下，仍然未知。那，我们建议在健康的体细胞（包括雄性与雌性细胞）中解解转座子如何控制转座子，以及该控制的丧失如何影响脊椎动物的健康和疾病。为了探索这个问题，我的小组将在动物中使用“ OMICS”方法，机器学习和实验验证的独特组合型号。我们使用两个脊椎动物模型来分别具有强度：实验室鼠标（例如功能强大遗传学，经过验证的抗体等）和非洲绿松石Killifish，这是一种自然短暂的模型有机体已经有助于开发（例如短期/寿命，应变多样性，成本效益等）。首先，我们会的跨座子活性的破译性二态调节，确定性腺骑马与性的影响 - 这种调节的染色体。其次，我们将使用功能基因组学来确定体细胞中的转座子活性。最后，我们将评估转座控制在关键体细胞中的影响组织和跨性别的终身脊椎动物健康，使用天然短暂的非洲绿松石杀死模型。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允许我们维持年轻和健康的基因组调节来防止其在疾病中的正调风景。 1