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A Fluorescence-based Lymphocyte Assay Suitable for High-throughput Screening of Small Molecules
Published on: March 10, 2017
In vitro screening for compounds that enhance human L1 mobilization
Natsuko Terasaki1, John L Goodier, Ling E Cheung
1Department of Biological Science, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Kanagawa, Japan.
Plos One
|September 17, 2013
Summary
Certain compounds can activate Long interspersed element 1 (L1) retrotransposons, potentially causing genomic mutations. This study screened 95 compounds, finding 15 that enhanced L1 activity, with three significantly increasing L1 retrotransposition, highlighting risks in drug safety.
Area of Science:
- Genomics and Molecular Biology
- Epigenetics and Transposable Elements
- Toxicology and Drug Safety
Background:
- Long interspersed element 1 (LINE1 or L1) retrotransposons comprise 17% of the human genome and can mobilize, acting as endogenous mutagens.
- L1 insertions can lead to genomic instability and disease, with their activity potentially induced by cellular stresses.
- Understanding factors that influence L1 transcription and retrotransposition is crucial for assessing genomic integrity and potential health risks.
Purpose of the Study:
- To screen a diverse library of 95 compounds for their ability to enhance human L1 transcription.
- To investigate the impact of selected compounds on L1 retrotransposition activity.
- To identify specific chemical agents and drugs that modulate L1 element activity.
Main Methods:
- Utilized a reporter gene assay in HepG2 cells to screen compounds for L1 promoter activity.
- Assessed 95 compounds, including genotoxic agents, cellular stress inducers, and commercial drugs.
- Developed a high-throughput real-time retrotransposition assay using a secreted Gaussia luciferase reporter.
Main Results:
- Fifteen compounds significantly increased L1 promoter activity (>1.5-fold) after 6 or 24 hours.
- Genotoxic agents, PPARα agonists (bezafibrate, fenofibrate), and NSAIDs (diflunisal, salicylamide, sulindac) were notable inducers of L1 transcription.
- Three compounds (etomoxir, WY-14643, salicylamide) significantly enhanced L1 retrotransposition.
Conclusions:
- This study is the first to comprehensively report the effects of various compounds on L1 transcription and retrotransposition.
- Certain chemical and drug-induced stresses can potentially cause genomic mutations by mobilizing L1 elements.
- The findings underscore the importance of considering induced L1 transcription and retrotransposition in drug safety evaluations and environmental risk assessments.
