| Autor: |
Stefanova ME; Development and Disease Research Group, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.; Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany., Ing-Simmons E; MRC London Institute of Medical Sciences, Du Cane Road, London W12 0NN, UK.; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK., Stefanov S; Berlin Institute for Molecular and Systems Biology, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.; Department of Biology, Chemistry, and Pharmacology, Institute of Biochemistry, Freie Universität Berlin, 14163 Berlin, Germany., Flyamer I; Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland., Dorado Garcia H; Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin, 13125 Berlin, Germany.; Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, 13353 Berlin, Germany.; Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany., Schöpflin R; Development and Disease Research Group, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.; Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany., Henssen AG; Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin, 13125 Berlin, Germany.; Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, 13353 Berlin, Germany.; Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.; German Cancer Consortium (DKTK), Partner Site Berlin, and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Vaquerizas JM; MRC London Institute of Medical Sciences, Du Cane Road, London W12 0NN, UK.; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK., Mundlos S; Development and Disease Research Group, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.; Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. |
| Abstrakt: |
In this study, we delve into the impact of genotoxic anticancer drug treatment on the chromatin structure of human cells, with a particular focus on the effects of doxorubicin. Using Hi-C, ChIP-seq, and RNA-seq, we explore the changes in chromatin architecture brought about by doxorubicin and ICRF193. Our results indicate that physiologically relevant doses of doxorubicin lead to a local reduction in Hi-C interactions in certain genomic regions that contain active promoters, with changes in chromatin architecture occurring independently of Top2 inhibition, cell cycle arrest, and differential gene expression. Inside the regions with decreased interactions, we detected redistribution of RAD21 around the peaks of H3K27 acetylation. Our study also revealed a common structural pattern in the regions with altered architecture, characterized by two large domains separated from each other. Additionally, doxorubicin was found to increase CTCF binding in H3K27 acetylated regions. Furthermore, we discovered that Top2-dependent chemotherapy causes changes in the distance decay of Hi-C contacts, which are driven by direct and indirect inhibitors. Our proposed model suggests that doxorubicin-induced DSBs cause cohesin redistribution, which leads to increased insulation on actively transcribed TAD boundaries. Our findings underscore the significant impact of genotoxic anticancer treatment on the chromatin structure of the human genome. |
