Activation of retrotransposable elements in cellular senescence and aging

Brown University, Providence RI

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): Retrotransposable elements (RTEs) comprise approximately 45% of the human genome. RTEs are mobile DNA elements that can insert into new genomic positions using a copy and paste mechanism. This process, termed retrotransposition, can be deleterious at multiple levels by causing mutagenesis and genome structural instability, triggering epigenetic changes, and disrupting normal patterns of gene regulation. Numerous single- gene mutations in humans have been documented to result from germline retrotransposition. Organisms have evolved multiple transcriptional and post-transcriptional silencing mechanisms to protect their genomes against RTEs. Until recently RTEs were thought to be silent in the soma, however, new evidence points to activity in the brain and in cancer cells. Indeed, initial indications are that somatic retrotransposition is much more frequent than previously anticipated. We have reported that retrotransposition is activated during aging and cellular senescence, and hypothesized that it may represent a hitherto unappreciated molecular aging process. The long-term goal of our research is to determine the impact of retrotransposition on genome integrity during aging. As a first step, my objective in thi proposal is to study, using high throughput DNA sequencing methods, the mobilization of RTEs during cellular senescence. In Aim 1 I will perform genome-wide profiling to determine where new insertions occur and evaluate whether these events have the potential to exert deleterious effects by disrupting regions of the genome important for cell function. In Aim 2 I will examine the occurrence of unique retrotranspositions in individual cells. We have evidence that many new insertions likely occur in individual post-mitotic cells after they have ceased dividing. To comprehensively profile the spectrum and frequency of these events I will use single-cell whole genome DNA sequencing. My research will employ innovative state-of-the-art high-throughput sequencing strategies, and I will develop new bioinformatic tools to integrate and validate the output from multiple algorithms. The information obtained will address the question: To what extent is retrotransposition damaging to the genomes of somatic cells in our bodies, and is this a plausible mechanism of aging? The experience gained and tools developed will be highly informative for future studies aimed at examining these processed directly in aging tissues. My efforts will also inform whether proof- of-principle studies using interventions that inhibit retrotransposition should be investigated as potential therapeutics for age-associated diseases.