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Retroviral Scanning: Mapping MLV Integration Sites to Define Cell-specific Regulatory Regions
Published on: May 28, 2017
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Enhancers are major targets for murine leukemia virus vector integration
Suk See De Ravin1, Ling Su, Narda Theobald
1Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Journal of Virology
|February 7, 2014
Summary
Murine leukemia virus (MLV)-based vectors preferentially integrate into active enhancers, not just transcription start sites. This finding explains the insertional mutagenesis risks associated with MLV gene therapy.
Area of Science:
- Gene Therapy
- Molecular Biology
- Epigenetics
Background:
- Murine leukemia virus (MLV)-based retroviral vectors are used in gene therapy but can cause insertional mutagenesis due to strong promoter/enhancer elements and integration site preferences.
- MLV integration was thought to prefer transcription start sites (TSS), but only a small fraction of integrations occurred there.
Purpose of the Study:
- To resolve the discrepancy between MLV integration preferences and observed integration sites.
- To create a high-resolution genome-wide map of MLV integration sites.
Main Methods:
- Generated a genome-wide integration map of over one million sites from CD34(+) hematopoietic stem cells transduced with an MLV-based vector.
- Analyzed integration site clusters and their association with histone modifications (H3K4me1, H3K27ac).
Main Results:
- Identified ~60,000 tight clusters of MLV integration sites, comprising ~1.9% of the genome.
- Found that 87% of integration sites are within histone H3K4me1 islands (enhancers).
- Observed that most clusters also possess H3K27ac marks, indicating active enhancers, with some targeting oncogene enhancers like LMO2.
Conclusions:
- Active enhancer regions are the primary targets for MLV integration.
- MLV preferentially integrates into regions favorable for viral gene expression.
- These findings provide insights into MLV integration target selection and explain the high risk of insertional mutagenesis in MLV gene therapy.
