MLV integration site selection is driven by strong enhancers and active promoters
Open accessAbstract
Retroviruses integrate into the host genome in patterns specific to each virus. Understanding the causes of these patterns can provide insight into viral integration mechanisms, pathology and genome evolution, and is critical to the development of safe gene therapy vectors. We generated murine leukemia virus integrations in human HepG2 and K562 cells and subjected them to second-generation sequencing, using a DNA barcoding technique that allowed us to quantify independent integration events. We characterized >3 700 000 unique integration events in two ENCODE-characterized cell lines. We find that integrations were most highly enriched in a subset of strong enhancers and active promoters. In both cell types, approximately half the integrations were found in <2% of the genome, demonstrating genomic influences even narrower than previously believed. The integration pattern of murine leukemia virus appears to be largely driven by regions that have high enrichment for multiple marks of active chromatin; the combination of histone marks present was sufficient to explain why some strong enhancers were more prone to integration than others. The approach we used is applicable to analyzing the integration pattern of any exogenous element and could be a valuable preclinical screen to evaluate the safety of gene therapy vectors.
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The integration preferences of HIV-1 for active transcription units and MLV for promoter/enhancer regions are largely dictated by specific interactions of their integrase proteins with chromatin-bound host factors.
“The well-understood integration preferences of HIV-1 for active transcription units72 and MLV for promoter/enhancer regions73–75 are in large part dictated via specific interactions of the respective IN proteins with chromatin-bound host factors.”
From Structure and function of retroviral integrase (2022) · cites this paper as [75]
The Results and Discussion report a strong MLV integration preference for particular strong enhancers and active promoters. The Results do not exclude an integrase–protein tether, and the Discussion describes BET proteins as possible tethers, but neither establishes that such interactions largely dictate MLV integration. The HIV-1 preference is separately cited in the citing sentence and is not assessed here. (LLM, conf=0.87)
Experimental — accuracy not yet measuredBET proteins stimulate gamma-retroviral integrase strand transfer in vitro and appear to act as bimodal tethers directing PICs to preferred genomic locations.
“BET proteins significantly stimulate γ-retroviral IN strand transfer activities in vitro67,115,116 and appear to act as bimodal tethers to direct PICs to preferred genomic locations74,75,114,117,118.”
From Structure and function of retroviral integrase (2022) · cites this paper as [75]
The Discussion (page unavailable) says BET proteins may serve as tethers guiding MLV integration, which supports the hedged tethering claim. It does not describe them as bimodal tethers or establish that they direct preintegration complexes to preferred locations. The in-vitro strand-transfer clause has separate citations in the citing sentence and is not attributed to this paper. (LLM, conf=0.84)
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SURVEY AND SUMMARY Molecular mechanisms of retroviral integration site selection
Kvaratskhelia, M., Sharma, A., Larue, R. C., Serrao, E., & Engelman, A. (2014)
Treating Hemophilia by Gene Therapy
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Enhort: a platform for deep analysis of genomic positions
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Peer Review #1 of "Enhort: a platform for deep analysis of genomic positions (v0.1)"
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Peer Review #2 of "Enhort: a platform for deep analysis of genomic positions (v0.2)"
(2019) · PeerJ Computer Science · doi:10.7287/peerj-cs.198v0.2/reviews/2
Zhang, H., Yang, L., Xu, J., & Yen, K. (2021) · Scientia Sinica Vitae · doi:10.1360/ssv-2021-0118
- Authors
- LaFave, M. C., Varshney, G. K., Gildea, D. E., Wolfsberg, T. G., Baxevanis, A. D., & Burgess, S. M.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Burgess, Shawn M.
- ORCID
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-01-23
- Volume
- 42
- Issue
- 7
- Pages
- 4257-4269
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC3985626
- OpenAlex
- W2034118113
- Cited by
- 114
- References
- 47
- Citations by year
- 2025: 3 · 2024: 8 · 2023: 8 · 2022: 6 · 2021: 8 · 2020: 5 · 2019: 14 · 2018: 9 · 2017: 10 · 2016: 20 · 2015: 15 · 2014: 8
- FWCI
- 11.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- public-domain
- Locations
- Nucleic Acids Research (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Human Genome Research Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- murine leukemia virus, retroviral integration, integration site selection, enhancers, histone modifications, active chromatin, DNA barcoding, HepG2 cells, K562 cells, integration hotspots
- MeSH terms
- Attachment Sites, Microbiological, Enhancer Elements, Genetic, Humans, Moloney murine leukemia virus, Promoter Regions, Genetic, Virus Integration, K562 Cells, Cell Line, Tumor
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