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Chromatin accessibility changes at intergenic regions associates with ovarian cancer drug resistance

John Gallon, Erick Loomis, View ORCID ProfileEdward Curry, Nicholas Martin, Leigh Brody, Ian Garner, View ORCID ProfileRobert Brown, James M. Flanagan
doi: https://doi.org/10.1101/2021.02.24.432641
John Gallon
1Ovarian Cancer Action Research Centre, Dept Surgery & Cancer, Imperial College London, London W12 8EE, UK
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Erick Loomis
1Ovarian Cancer Action Research Centre, Dept Surgery & Cancer, Imperial College London, London W12 8EE, UK
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Edward Curry
1Ovarian Cancer Action Research Centre, Dept Surgery & Cancer, Imperial College London, London W12 8EE, UK
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Nicholas Martin
2Trace Element Laboratory, Charing Cross Hospital, Imperial College NHS Trust, London, UK
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Leigh Brody
3Desktop Genetics, 28 Hanbury St, London E1 6QR, UK
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Ian Garner
1Ovarian Cancer Action Research Centre, Dept Surgery & Cancer, Imperial College London, London W12 8EE, UK
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Robert Brown
1Ovarian Cancer Action Research Centre, Dept Surgery & Cancer, Imperial College London, London W12 8EE, UK
4Institute of Cancer Research, Sutton, London SM2 5NG, UK
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  • For correspondence: b.brown@imperial.ac.uk
James M. Flanagan
1Ovarian Cancer Action Research Centre, Dept Surgery & Cancer, Imperial College London, London W12 8EE, UK
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  • For correspondence: b.brown@imperial.ac.uk
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Abstract

We have investigated how genomic distribution of chromatin accessibilities alter during acquisition of resistance to carboplatin-based chemotherapy using matched ovarian cell lines from high grade serous ovarian cancer (HGSOC) patients before and after becoming clinically resistant to platinum-based chemotherapy. Resistant lines show altered chromatin accessibility at intergenic regions, but less so at gene promoters. Super-enhancers, as defined by clusters of cis-regulatory elements, at these intergenic regions show chromatin changes that are associated with altered expression of linked genes, with enrichment for genes involved in the Fanconi anemia/BRCA DNA damage response pathway. Further, genome-wide distribution of platinum adducts associates with the chromatin changes observed and distinguish sensitive from resistant lines. In the resistant line, we observe fewer adducts around gene promoters and more adducts at intergenic regions. Thus, chromatin changes at intergenic regulators of gene expression are associated with in vivo derived drug resistance and Pt-adduct distribution in patient-derived HGSOC drug resistance models.

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  • ↵# The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 24, 2021.
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Chromatin accessibility changes at intergenic regions associates with ovarian cancer drug resistance
John Gallon, Erick Loomis, Edward Curry, Nicholas Martin, Leigh Brody, Ian Garner, Robert Brown, James M. Flanagan
bioRxiv 2021.02.24.432641; doi: https://doi.org/10.1101/2021.02.24.432641
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Chromatin accessibility changes at intergenic regions associates with ovarian cancer drug resistance
John Gallon, Erick Loomis, Edward Curry, Nicholas Martin, Leigh Brody, Ian Garner, Robert Brown, James M. Flanagan
bioRxiv 2021.02.24.432641; doi: https://doi.org/10.1101/2021.02.24.432641

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