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Retroviral Scanning: Mapping MLV Integration Sites to Define Cell-specific Regulatory Regions
Published on: May 28, 2017
3D hotspots of recurrent retroviral insertions reveal long-range interactions with cancer genes
Sepideh Babaei1, Waseem Akhtar2, Johann de Jong3
1Delft Bioinformatics Lab, Faculty of Electrical Engineering Mathematics and Computer Science, Delft University of Technology, Mekelweg 4, 2628 CD Delft, The Netherlands.
Abstract:
Genomically distal mutations can contribute to the deregulation of cancer genes by engaging in chromatin interactions. To study this, we overlay viral cancer-causing insertions obtained in a murine retroviral insertional mutagenesis screen with genome-wide chromatin conformation capture data. Here we find that insertions tend to cluster in 3D hotspots within the nucleus. The identified hotspots are significantly enriched for known cancer genes, and bear the expected characteristics of bona fide regulatory interactions, such as enrichment for transcription factor-binding sites. In addition, we observe a striking pattern of mutual exclusive integration. This is an indication that insertions in these loci target the same gene, either in their linear genomic vicinity or in their 3D spatial vicinity. Our findings shed new light on the repertoire of targets obtained from insertional mutagenesis screening and underline the importance of considering the genome as a 3D structure when studying effects of genomic perturbations.
Insights
Genomic mutations can deregulate cancer genes through 3D chromatin interactions. This study reveals viral insertions cluster in nuclear hotspots, targeting cancer genes and highlighting the genome's 3D structure in mutagenesis screens.
Area of Science:
- Genomics
- Cancer Biology
- Epigenetics
Background:
- Genomically distal mutations can deregulate cancer genes via chromatin interactions.
- Insertional mutagenesis screens identify viral insertions that contribute to cancer development.
Purpose of the Study:
- To investigate how distal mutations affect cancer genes by analyzing chromatin interactions.
- To understand the spatial organization of viral insertions within the nucleus.
Main Methods:
- Overlaying data from murine retroviral insertional mutagenesis screens with genome-wide chromatin conformation capture data.
- Analyzing the 3D clustering patterns of viral insertions.
Main Results:
- Viral insertions identified in insertional mutagenesis screens tend to cluster in specific 3D hotspots within the nucleus.
- These hotspots are significantly enriched for known cancer genes and regulatory elements like transcription factor-binding sites.
- A pattern of mutually exclusive integration was observed, indicating that insertions target the same gene regardless of linear or 3D proximity.
Conclusions:
- Genomic perturbations, such as viral insertions, can target cancer genes through 3D chromatin interactions.
- Understanding the genome's three-dimensional structure is crucial for interpreting insertional mutagenesis screening results and their impact on cancer gene regulation.
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