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

逆转录转座的体细胞激活：衰老的新分子机制？

基本信息

批准号：
9334684
负责人：
John M Sedivy
金额：
$ 195.37万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
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/9334684
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

项目摘要

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（由适用提供）：逆转录元素（RTE）占人类基因组的45％。它们是移动DNA元素，可以使用复制和粘贴机制插入新的基因组位点。该过程被称为逆转录，在多个级别上被删除。 RTE居住在所有生命形式的基因组中，从考古细菌到人类。毫不奇怪，多种防御机制已经进化以保护基因组免受RTE的影响。第一道防线是将元素驻留在反射异染色质中以防止其表达的基因组位置。结合其他转录后机制，这些防御能力非常有效，因此，绝大多数RTE已成为被动的基因组传球者，在进化时间内积累了突变。然而，大多数生物具有少数保持活跃的元素。在人类中，长长的核元素1（LINE-1）。新的L1插入以每数百个出生的一个频率发生，并且已经证明了许多单基因突变是由于我们的细菌活性导致的。我们的时机情况如何？从历史上看，对此几乎没有关注，普遍的观点是RTE在很大程度上处于休眠状态。然而，在各种体细胞环境中，越来越多地发现了L1转录甚至从头插入的压抑，包括胚胎发生，成人大脑和某些干细胞。在癌症中，新的L1插入发生在多种肿瘤类型中。我们团队的四名成员（Sedivy，Gorbunova，Helfand和Seluanov）最近发表了证据，表明RTE在衰老，在人类细胞，苍蝇和小鼠中变得活跃。为了支持，迅速积累的文献表明，体细胞转载置次置位比以前预期的要频繁得多，并且其在衰老过程中的激活是深处的。借助逆转录转座子专家Jef Boeke，我们提出了这样一种假设，即逆转录的体细胞激活是一种新颖且迄今未批准的分子老化过程。我们的工作和其他工作提出的基本机制是异染色质的衰老相关的折衷，导致其反射能力的反射能力和丧失。该计划项目赠款（PPG）提案的目标是阐明RTE生物学的这一新方面。我们将三个项目汇总在一项高度综合的研究计划中，该计划利用潜水模型系统（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，通过分子生物学到小鼠生理）。该PPG进行的研究将：1）定义老年组织和感觉细胞中的“体细胞逆转录景观”； 2）研究导致随着年龄的增长的宿主防御系统失败的机制； 3）研究RTE激活对细胞和组织功能的下游后果； 4）探索干预措施的策略，以减轻RTE激活可能引起的年龄相关条件。转座通工程和基因组学核心以及小鼠干预和老化核心将提供关键和集中的服务以支持这项研究。