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.

Public Health Relevance

Retrotransposable elements (RTEs) are virus-like parasites that have invaded our genomes. They can have deleterious consequences on our health, and are hence held in check by a variety of mechanisms. The goal of this Program is to study how these mechanisms fail during aging, determine in detail the results of this failure, and investigat what could be done therapeutically to mitigate the consequences. Our interdisciplinary research will explore these fundamental questions in Drosophila and mammalian (mouse) models of aging, using wide-ranging methods from basic physiology to high-throughput genomic tools. REVIEW OF INDIVIDUAL COMPONENTS OF THE PROGRAM PROJECT CORE A: ADMINISTRATIVE CORE; Dr. John Sedivy, Core Leader (CL) DESCRIPTION (provided by applicant): The overall goals of the Administrative Core (Core A) are to provide scientific, programmatic and fiscal leadership, facilitate lines of communication between the different researchers involved in the PPG, maintain coherence in the PPG's overall and long-range goals, and ensure that resources resulting from the PPG will benefit the scientific community. Core A will thus provide the mechanisms to manage, evaluate, and evolve the three Research Projects and two Research Cores in the program. In the context of the above, the task of Core A will be the effective coordination of the activities of all the components, such as the selection and design of jointly used models and resources (mouse lines, transposon reporters, sequencing strategies, etc.), the development of new technologies and tools to more effectively promote the research goals, providing statistical services to the members of the PPG, and enabling the scientific community access to the PPG's resources, technologies, and databases. The following activities will also contribute to achieving the overall goals: 1) Core A will ensure that the administrative and financial requirements of the NIH and the participating institutions are met; 2) Core A will organize monthly videoconferences and annual face-to-face retreats; 3) Core A will be responsible for communications between the PPG and the NIH; 4) Core A will facilitate the submission of joint publications and, in collaboration with Core B, the deposition of high-throughput datasets into public databases; 5) Core A will establish the External Advisory Board (EAB) and organize the annual reviews of the PPG.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1)
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Guo, Max
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Brown University
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Seluanov, Andrei; Gladyshev, Vadim N; Vijg, Jan et al. (2018) Mechanisms of cancer resistance in long-lived mammals. Nat Rev Cancer 18:433-441
Wood, Jason G; Schwer, Bjoern; Wickremesinghe, Priyan C et al. (2018) Sirt4 is a mitochondrial regulator of metabolism and lifespan in Drosophila melanogaster. Proc Natl Acad Sci U S A 115:1564-1569
Sun, Xiaoji; Wang, Xuya; Tang, Zuojian et al. (2018) Transcription factor profiling reveals molecular choreography and key regulators of human retrotransposon expression. Proc Natl Acad Sci U S A 115:E5526-E5535
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Gorbunova, Vera; Seluanov, Andrei (2016) DNA double strand break repair, aging and the chromatin connection. Mutat Res 788:2-6