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

基本信息

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
项目类别：
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

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

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项目摘要

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（由适用提供）：几乎构成人类基因组的一半，转座子是几乎所有动物基因组中最丰富的居民。这些提出的自私的“垃圾” DNA序列代表了能够对基因组稳定性和完整性造成严重破坏的潜在诱变来源。尽管大量的研究工作表明生殖细胞利用了生殖线特异性的小RNA系统，即PIRNA途径，以使动物性腺中的转座子沉默，但我们对转座子活性和控制体细胞中转座子的机制几乎没有任何惊喜。长期以来，人们一直认为转座几乎没有在体细胞中移动。该结论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，在正常的神经发生和胚胎发生过程中发生换位。我们的初步数据表明，在果蝇发育过程中，体细胞组织和卵巢中存在相当数量的插入事件。有趣的是，已经证明，在环境应激或肿瘤发生过程中，转座子在老年细胞中变得高度活跃。这些观察结果提高了转座子有助于动物发育，衰老和疾病进展的引人入胜的潜力。为了检验这一假设，我将首先建立一个强大的平台用单细胞分辨率捕获单个换位事件并确定其插入位点基本对分辨率（AIM 1）。基于令人鼓舞的初步数据，我们将在第二个目标中使用我们的平台来研究星形胶质细胞中的转座子活动，并探索这些最丰富的脑细胞中转座子的潜在功能。为了了解构成体细胞组织转座子控制的机制，我还将执行一个基因组宽的诱变筛选，以识别驯服转座子所需的成分。在第三个目标中，我将重点关注衰老期间的转座子活性，这是许多破坏性疾病的主要因素，并检查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来治疗疾病的新观点。