Somatic structural variant formation is guided by and influences genome architecture
- Nikos Sidiropoulos1,2,9,
- Balca R. Mardin3,4,9,
- F. Germán Rodríguez-González1,2,
- Ivan D. Bochkov5,
- Shilpa Garg6,
- Adrian M. Stütz3,
- Jan O. Korbel3,
- Erez Lieberman Aiden5,7 and
- Joachim Weischenfeldt1,2,8
- 1Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen 2200, Denmark;
- 2The Finsen Laboratory, Rigshospitalet, Copenhagen 2200, Denmark;
- 3European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany;
- 4BioMed X Institute, 69120 Heidelberg, Germany;
- 5The Center for Genome Architecture, Baylor College of Medicine, Houston, Texas 77030, USA;
- 6Department of Biology, University of Copenhagen, Copenhagen 2200, Denmark;
- 7Center for Theoretical Biological Physics, Rice University, Houston, Texas 77030, USA;
- 8Department of Urology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
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↵9 These authors contributed equally to this work.
Abstract
The occurrence and formation of genomic structural variants (SVs) is known to be influenced by the 3D chromatin architecture, but the extent and magnitude have been challenging to study. Here, we apply Hi-C to study chromatin organization before and after induction of chromothripsis in human cells. We use Hi-C to manually assemble the derivative chromosomes following the occurrence of massive complex rearrangements, which allows us to study the sources of SV formation and their consequences on gene regulation. We observe an action–reaction interplay whereby the 3D chromatin architecture directly impacts the location and formation of SVs. In turn, the SVs reshape the chromatin organization to alter the local topologies, replication timing, and gene regulation in cis. We show that SVs have a strong tendency to occur between similar chromatin compartments and replication timing regions. Moreover, we find that SVs frequently occur at 3D loop anchors, that SVs can cause a switch in chromatin compartments and replication timing, and that this is a major source of SV-mediated effects on nearby gene expression changes. Finally, we provide evidence for a general mechanistic bias of the 3D chromatin on SV occurrence using data from more than 2700 patient-derived cancer genomes.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.275790.121.
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Freely available online through the Genome Research Open Access option.
- Received May 18, 2021.
- Accepted February 11, 2022.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
