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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？

基本信息

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
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/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

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.