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）：逆转录转座因子（RTE）占人类基因组的约45%。它们是移动的DNA元件，可以使用复制和粘贴机制插入新的基因组位点。这一过程被称为反转录转座，在多个层面上都是有害的。RTE存在于所有生命形式的基因组中，从古细菌到人类。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。第一道防线是将这些元件所在的基因组位置整合到抑制性异染色质中，以防止它们的表达。结合其他转录后机制，这些防御非常有效，因此绝大多数RTE已经成为被动的基因组乘客，在进化过程中积累突变。然而，大多数生物体都含有少量保持活性的元素;在人类中，长散布的核元素-1（LINE-1）。新的L1插入发生的频率是每几百个新生儿中有一个，并且已经记录了许多单基因突变是由我们的生殖细胞中的L1活性引起的。我们组织中的情况是什么？从历史上看，很少有人注意到这一点，流行的观点是，RTE在很大程度上是休眠的。然而，L1转录的去抑制，甚至从头插入越来越多地被发现在各种体细胞的情况下，包括胚胎发生，成人脑，和一些干细胞。在癌症中，新的L1插入发生在各种肿瘤类型中。我们团队的四名成员（Sedivy，Gorbunova，Helfand和Seluanov）最近发表了证据，证明在人类细胞，苍蝇和小鼠中，RTEs在衰老过程中变得活跃。支持，一个快速积累的文献表明，体细胞逆转录转座比以前预期的要频繁得多，它的激活在衰老过程中是非常保守的。我们与反转录转座子专家杰夫·博克（Jef Boeke）一起提出了这样的假设：反转录转座的体细胞激活是一种新颖且迄今为止尚未被认识到的分子衰老过程。我们和其他人的工作表明，潜在的机制是异染色质老化相关的妥协，导致其去浓缩和抑制能力的丧失。这个计划项目资助（PPG）提案的目标是阐明RTE生物学的这个新的和迷人的方面。我们将三个项目汇集在一个高度集成的研究计划中，该计划利用不同的模型系统（从果蝇，通过哺乳动物细胞培养到小鼠）和调查方法（从高通量基因组学，通过分子生物学到小鼠生理学）。该PPG进行的研究将：1）定义衰老组织和衰老细胞中的“体细胞逆转录景观”; 2）调查导致宿主防御系统随年龄增长而失败的机制; 3）研究RTE激活对细胞和组织功能的下游后果; 4）探索干预策略，以减轻可能由RTE激活引起的与年龄相关的疾病。转座子工程和基因组学核心和小鼠干预和衰老核心将提供关键和集中的服务，以支持这项研究。