Somatic transposition-mediated genome variegation during development, disease and aging conditions

发育、疾病和衰老条件下体细胞转座介导的基因组变异

• 批准号: 9349391
• 负责人: Zhao Zhang
• 金额: $ 41.25万
• 依托单位: CARNEGIE INSTITUTION OF WASHINGTON, D.C.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9349391
• 关键词: Address; Affect; Aging; Alpha Cell; Animals; Astrocytes; Award; Base Pairing; Brain; Cardiovascular Diseases; Cells; DNA; DNA Damage; DNA Sequence; Data; Development; Disease; Disease Progression; Drosophila genus; Drosophila melanogaster; Elements; Embryonic Development; Event; Evolution; Gene Expression; Generations; Genes; Genetic; Genome; Genome Stability; Genomic Instability; Genomics; Germ Cells; Goals; Gonadal structure; Homeostasis; Human Genome; Immune system; Induced Mutation; Junk DNA; Knowledge; Label; Learning; Malignant Neoplasms; Mammals; Measures; Mediating; Modeling; Monitor; Mus; Mutagenesis; Mutation; Neurodegenerative Disorders; Ovarian Follicle; Ovary; Pathway interactions; Play; Population; Publications; Reporting; Repression; Research; Research Personnel; Resolution; Resources; Role; Science; Site; Small RNA; Somatic Cell; Source; Stress; System; Testing; Therapeutic; Time; Tissues; Vertebrates; Work; base; brain cell; cell age; cell type; experience; experimental study; fly; genome integrity; genome-wide; genome-wide analysis; human disease; mind control; neurogenesis; neuronal cell body; novel; piRNA; public health relevance; tool; tumorigenesis

 DESCRIPTION (provided by applicant): Making up almost half of the human genome, transposons are the most abundant residents in almost all animal genomes. These presumed selfish "junk" DNA sequences represent a potential mutagenic source able to wreak havoc on genome stability and integrity. While a significant amount of research work has shown that germ cells exploit a germline specific small RNA system, the piRNA pathway, to silence transposons in animal gonads, we know surprisingly little about transposon activity and the mechanisms that control transposons in somatic tissues. It has long been assumed that transposons barely move in somatic cells. This conclusion could largely be due to the insensitive tools that have been used to measure transposon mobilization. Recently, increasing evidence suggests that transposition occurs during normal neurogenesis and embryogenesis. Our preliminary data suggest that there are comparable numbers of insertion events in somatic tissues and ovaries during fruit fly development. Interestingly, it has been documented that transposons become highly active in aged cells, following environmental stress or during tumorigenesis. These observations raise the intriguing possibility that transposons contribute to animal development, aging and disease progression. To test this hypothesis, I will first establish a robust platform to capture single transposition events with single cell resolution and determine their insertion sites with base-pair resolution (aim 1). Based on the encouraging preliminary data we have, in the second aim, I will apply our platform to study transposon activities in astrocytes and explore potential functions of transposons in these most abundant brain cells. To understand mechanisms that underlie transposon control in somatic tissue, I will also perform a genome wide mutagenesis screen to identify the components that are required to tame transposons. In the third aim, I will focus on the transposon activities during aging, which is a primary factor fo many devastating diseases, and examine the potential impacts of transposons on aging and aging-associated disease. Collectively, these studies develop new tools to study transposon activity and potential function, characterize new paradigms to understand animal development, aging and disease progression, and potentially provide new perspective to treat diseases by harnessing transposons.

 描述（申请人提供）：转座子几乎占人类基因组的一半，是几乎所有动物基因组中最丰富的居民。这些假定的自私的“垃圾”DNA序列代表了一个潜在的诱变源，能够对基因组的稳定性和完整性造成严重破坏。虽然大量的研究工作表明，生殖细胞利用生殖系特异性小RNA系统，皮尔纳途径，沉默动物性腺中的转座子，但我们对转座子活性和控制体细胞组织中转座子的机制知之甚少。长期以来，人们一直认为转座子在体细胞中几乎不移动。这一结论在很大程度上可能是由于用于测量转座子动员的不敏感工具。最近，越来越多的证据表明，转座发生在正常的神经发生和胚胎发生。我们的初步数据表明，有相当数量的插入事件在果蝇发育过程中的体细胞组织和卵巢。有趣的是，已经证明转座子在老化细胞中，在环境压力或肿瘤发生期间变得高度活跃。这些观察结果提出了一个有趣的可能性，即转座子有助于动物发育，衰老和疾病进展。为了验证这个假设，我将首先建立一个强大的平台， 以单细胞分辨率捕获单个转座事件并确定其插入位点 与碱基对分辨率（目标1）。基于我们所拥有的令人鼓舞的初步数据，在第二个目标中，我将应用我们的平台研究星形胶质细胞中的转座子活性，并探索转座子在这些最丰富的脑细胞中的潜在功能。为了了解体细胞组织中转座子控制的机制，我还将进行全基因组诱变筛选，以确定驯服转座子所需的组件。在第三个目标中，我将关注衰老过程中的转座子活动，这是许多毁灭性疾病的主要因素，并研究转座子对衰老和衰老相关疾病的潜在影响。总的来说，这些研究开发了研究转座子活性和潜在功能的新工具，表征了了解动物发育，衰老和疾病进展的新范式，并可能通过利用转座子治疗疾病提供新的视角。