# Regulation of retrotransposable element activity in cellular senescence and aging.

> **NIH NIH P01** · BROWN UNIVERSITY · 2020 · $363,788

## Abstract

PROJECT SUMMARY (PROJECT 1)
Retrotransposable elements (RTEs) comprise ~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 retro-
transposition, can be deleterious at multiple levels by causing mutagenesis and genome structural instability,
triggering epigenetic changes, and disrupting normal patterns of gene regulation. Organisms have evolved
multiple transcriptional and post-transcriptional silencing mechanisms to protect their genomes. 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. Our group has reported that retrotransposition is activated during aging and cellular senescence,
and hypothesized that it may represent a hitherto unappreciated molecular aging process. These findings
however raise important new questions: what is the magnitude of the 'retrotransposition problem', and to what
extent is this process damaging to our somatic cells? What are the mechanisms that hold RTEs in check in
somatic tissues, and how do they fail with age? Our lack of knowledge in these areas is a key barrier to under-
standing the role of RTEs in aging and disease. To break new ground in these efforts our research seeks to
elucidate what we broadly refer to as 'the landscape of somatic retrotransposition'. In Aim 1 we will perform a
genome-wide quantitative analysis of novel transpositions. The frequency of these events in the genomes of
senescent or aged cells, their structures, and their locations are completely unknown. With Jef Boeke and Core
B we will apply high-throughput DNA sequencing, including TIP-seq and single-cell whole genome sequencing
to comprehensively profile novel transposition events. As an independent method we will use retrotransposon
reporters. Aim 2 is based on our preliminary data that occupancy of pRb on the L1 promoter decreases in
senescent human cells and aging mouse tissues, that overexpression of pRb antagonizes the activation of L1
in senescent cells, and knockdown in normal cells promotes L1 activation. We hypothesize that pRb, a known
regulator heterochromatin, represses L1 in normal cells and that this mechanism fails during senescence and
aging. We will therefore examine the composition of pRb-containing complexes and their interaction with L1s,
observe their behavior during cellular senescence and mouse aging, and perturb specific components to test
effects on L1 activity. In Aim 3 we will modulate RTE activity using genetic and pharmaceutical interventions
and investigate the consequences on cellular function. We will use engineered regulatable L1 elements to
drive increased retrotransposition activity, develop shRNA or CRISPR interventions to block the transcription of
endogenous L1s, and treat cells and mice with reverse tra...

## Key facts

- **NIH application ID:** 9956957
- **Project number:** 5P01AG051449-05
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** John M Sedivy
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $363,788
- **Award type:** 5
- **Project period:** — → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9956957

## Citation

> US National Institutes of Health, RePORTER application 9956957, Regulation of retrotransposable element activity in cellular senescence and aging. (5P01AG051449-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9956957. Licensed CC0.

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