Somatic Activation of Retrotransposition: A new Molecular Mechanism of Aging?

逆转录转座的体细胞激活：一种新的衰老分子机制？

• 批准号: 9522255
• 负责人: John M Sedivy
• 金额: $ 17.39万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9522255
• 关键词: Adult; Affect; Age; Aging; Aging-Related Process; Applications Grants; Archaea; Attention; Autophagocytosis; Bioinformatics; Biological Models; Biology; Birth; Brain; Cell Culture Techniques; Cells; Chromatin; Cicatrix; Collaborations; Colorectal; Communication; Communities; DNA Damage; DNA Transposable Elements; Data Set; Databases; Defense Mechanisms; Deposition; Development; Drosophila genus; Elements; Embryo; Embryonic Development; Engineering; Ensure; Epigenetic Process; Evolution; Failure; Fibroblasts; Fossils; Frequencies; Gene Mutation; Genetic; Genetic Transcription; Genome; Genomic Instability; Genomics; Germ Lines; Goals; Health; Heterochromatin; High-Throughput Nucleotide Sequencing; Homeostasis; Homo sapiens; Host Defense; Human; Human Genome; Image; Incidence; Individual; Institution; Interdisciplinary Study; Intervention; Invaded; Investigation; Joints; L1 Elements; Lead; Leadership; Life; Light; Literature; Live Birth; Location; Longevity; Malignant Neoplasms; Mammalian Cell; Measures; Methods; Modeling; Molecular; Molecular Biology; Mus; Mutagenesis; Mutation; Nuclear; Nucleic Acids; Organism; Ovarian; Parasites; Paste substance; Performance; Pharmacology; Physiology; Process; Program Research Project Grants; Program Reviews; Prostate; Proteins; Publications; Publishing; Race; Repetitive Sequence; Reporter; Reporting; Repression; Research; Research Personnel; Research Project Grants; Research Support; Resources; Retinoblastoma Protein; Retreatment; Retrotransposition; Retrotransposon; Role; Science; Services; Site; Somatic Cell; Stem cells; Stress; System; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; United States National Institutes of Health; Videoconferences; Viral; Virus; Work; aged; base; chromatin modification; combat; derepression; design; epigenetic regulation; fascinate; fly; gene therapy; genomic tools; improved; member; mouse model; new technology; novel; prevent; programs; public health relevance; senescence; small hairpin RNA; statistical service; tool; transposon/insertion element; tumor

 DESCRIPTION (provided by applicant): Retrotransposable elements (RTEs) comprise ~45% of the human genome. They are mobile DNA elements that can insert into new genomic sites using a copy and paste mechanism. This process, known as retrotransposition, is deleterious at multiple levels. RTEs inhabit the genomes of all life forms, from archaebacteria to humans. Not surprisingly, multiple defense mechanisms have evolved to protect genomes against RTEs. The first line of defense is to incorporate the genomic locations where the elements reside into repressive heterochromatin to prevent their expression. Combined with other posttranscriptional mechanisms these defenses are quite effective, and hence the great majority of RTEs have become passive genome passengers, accumulating mutations over evolutionary time. Most organisms, however, harbor a small number of elements that remain active; in humans, the long interspersed nuclear element-1 (LINE-1). New L1 insertions occur at a frequency of one per several hundred births, and numerous single-gene mutations have been documented to result from L1 activity in our germlines. What is the situation in our tissues? Historically, little attenion has been given to this, the prevailing opinion being that RTEs were largely dormant. However, derepression of L1 transcription and even de novo insertions are increasingly being found in a variety of somatic contexts, including embryogenesis, adult brain, and some stem cells. In cancer new L1 insertions occur in a variety of tumor types. Four members of our team (Sedivy, Gorbunova, Helfand, and Seluanov) have recently published evidence that RTEs become active during aging, in human cells, flies, and mice. In support, a rapidly accumulating literature shows that somatic retrotransposition is much more frequent than previously anticipated, and that its activation during aging is deeply conserved. With Jef Boeke, a retrotransposon expert, we have developed the hypothesis that the somatic activation of retrotransposition is a novel and hitherto unappreciated molecular aging process. The underlying mechanism, suggested by our work and that of others, is an aging-associated compromise of heterochromatin, leading to its decondensation and loss of repressive capacity. The goal of this Program Project Grant (PPG) proposal is to shed light on this new and fascinating aspect of RTE biology. We bring together three Projects in a highly integrated research plan that exploits diverse model systems (from Drosophila, through mammalian cell culture to the mouse) and methods of inquiry (from high-throughput genomics, through molecular biology to mouse physiology). The research performed by this PPG will: 1) Define the 'landscape of somatic retrotransposition' in aged tissues and senescent cells; 2) Investigate the mechanisms that lead to the failure of host defense systems with age; 3) Study the downstream consequences of RTE activation on cellular and tissue function; 4) Explore strategies for interventions to alleviate age-associated conditions that may arise from RTE activation. A Transposon Engineering and Genomics Core and a Mouse Interventions and Aging Core will provide critical and centralized services to support this research.

 描述（由申请人提供）：逆转录转座元件（RTE）占人类基因组的约 45%，它们是可移动的 DNA 元件，可以使用复制和粘贴机制插入新的基因组位点，这一过程（称为逆转录转座）是有害的。 RTE 存在于从古细菌到人类的所有生命形式的基因组中，毫不奇怪，已经进化出多种防御机制来保护基因组免受 RTE 的侵害。这些元件驻留在抑制性异染色质中以防止其表达，与其他转录后机制相结合，这些防御非常有效，因此绝大多数 RTE 已成为被动的基因组乘客，在进化过程中积累突变。少数保持活性的元件；在人类中，长散布的核元件-1 (LINE-1) 的插入频率为每数百个新生儿中就有一个，并且已记录了许多单基因突变。历史上，人们很少关注这一点，普遍认为 RTE 基本上处于休眠状态，然而，L1 转录的去抑制甚至从头插入正在日益增多。我们团队的四名成员（Sedivy、Gorbunova、 Helfand 和 Seluanov）最近发表的证据表明，在人类细胞、果蝇和小鼠中，RTE 在衰老过程中变得活跃，快速积累的文献表明，体细胞逆转录转座比之前预期的要频繁得多，并且它在衰老过程中被激活。我们与逆转录转座子专家 Jef Boeke 一起提出了这样的假设：逆转录转座子的体细胞激活是一种新颖且迄今为止未被认识到的分子衰老过程，这是我们的工作所提出的。其他人认为，这是一种与衰老相关的异染色质损害，导致其解凝和抑制能力丧失。本项目拨款 (PPG) 提案的目标是阐明 RTE 生物学的这一新的、令人着迷的方面。将三个项目结合在一个高度集成的研究计划中，利用不同的模型系统（从果蝇，到哺乳动物细胞培养到小鼠）和探究方法（从高通量基因组学，到分子生物学到小鼠生理学）进行研究。通过该 PPG 将： 1) 定义衰老组织和衰老细胞中的“体细胞逆转座景观”； 2) 研究导致宿主防御系统随年龄增长而失效的机制； 3) 研究 RTE 激活对细胞的下游影响4) 探索干预策略，以缓解 RTE 激活可能引起的与年龄相关的疾病 转座子工程和基因组学核心以及小鼠干预和衰老核心将提供关键和集中的服务来支持。这项研究。