Rewiring of the 3D genome during acquisition of carboplatin resistance in a triple-negative breast cancer patient-derived xenograft
Abstract Changes in the three-dimensional (3D) structure of the genome are an emerging hallmark of cancer. Cancer-associated copy number variants and single nucleotide polymorphisms promote rewiring of chromatin loops, disruption of topologically associating domains (TADs), active/inactive chromatin...
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Nature Portfolio
2023-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-32568-7 |
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| author | Mikhail G. Dozmorov Maggie A. Marshall Narmeen S. Rashid Jacqueline M. Grible Aaron Valentine Amy L. Olex Kavita Murthy Abhijit Chakraborty Joaquin Reyna Daniela Salgado Figueroa Laura Hinojosa-Gonzalez Erika Da-Inn Lee Brittany A. Baur Sushmita Roy Ferhat Ay J. Chuck Harrell |
| author_facet | Mikhail G. Dozmorov Maggie A. Marshall Narmeen S. Rashid Jacqueline M. Grible Aaron Valentine Amy L. Olex Kavita Murthy Abhijit Chakraborty Joaquin Reyna Daniela Salgado Figueroa Laura Hinojosa-Gonzalez Erika Da-Inn Lee Brittany A. Baur Sushmita Roy Ferhat Ay J. Chuck Harrell |
| author_sort | Mikhail G. Dozmorov |
| collection | DOAJ |
| description | Abstract Changes in the three-dimensional (3D) structure of the genome are an emerging hallmark of cancer. Cancer-associated copy number variants and single nucleotide polymorphisms promote rewiring of chromatin loops, disruption of topologically associating domains (TADs), active/inactive chromatin state switching, leading to oncogene expression and silencing of tumor suppressors. However, little is known about 3D changes during cancer progression to a chemotherapy-resistant state. We integrated chromatin conformation capture (Hi-C), RNA-seq, and whole-genome sequencing obtained from triple-negative breast cancer patient-derived xenograft primary tumors (UCD52) and carboplatin-resistant samples and found increased short-range (< 2 Mb) interactions, chromatin looping, formation of TAD, chromatin state switching into a more active state, and amplification of ATP-binding cassette transporters. Transcriptome changes suggested the role of long-noncoding RNAs in carboplatin resistance. Rewiring of the 3D genome was associated with TP53, TP63, BATF, FOS-JUN family of transcription factors and led to activation of aggressiveness-, metastasis- and other cancer-related pathways. Integrative analysis highlighted increased ribosome biogenesis and oxidative phosphorylation, suggesting the role of mitochondrial energy metabolism. Our results suggest that 3D genome remodeling may be a key mechanism underlying carboplatin resistance. |
| format | Article |
| id | doaj-art-1d1cdc9046944ac6ba8d721377b361eb |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2023-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-1d1cdc9046944ac6ba8d721377b361eb2024-12-22T12:27:46ZengNature PortfolioScientific Reports2045-23222023-04-0113111710.1038/s41598-023-32568-7Rewiring of the 3D genome during acquisition of carboplatin resistance in a triple-negative breast cancer patient-derived xenograftMikhail G. Dozmorov0Maggie A. Marshall1Narmeen S. Rashid2Jacqueline M. Grible3Aaron Valentine4Amy L. Olex5Kavita Murthy6Abhijit Chakraborty7Joaquin Reyna8Daniela Salgado Figueroa9Laura Hinojosa-Gonzalez10Erika Da-Inn Lee11Brittany A. Baur12Sushmita Roy13Ferhat Ay14J. Chuck Harrell15Department of Biostatistics, Virginia Commonwealth UniversityDepartment of Biostatistics, Virginia Commonwealth UniversityDepartment of Pathology, Virginia Commonwealth UniversityDepartment of Pathology, Virginia Commonwealth UniversityDepartment of Pathology, Virginia Commonwealth UniversityC. Kenneth and Dianne Wright Center for Clinical and Translational Research, Virginia Commonwealth UniversityCenter for Cancer Immunotherapy and Autoimmunity, La Jolla Institute for ImmunologyCenter for Cancer Immunotherapy and Autoimmunity, La Jolla Institute for ImmunologyCenter for Cancer Immunotherapy and Autoimmunity, La Jolla Institute for ImmunologyCenter for Cancer Immunotherapy and Autoimmunity, La Jolla Institute for ImmunologyCenter for Cancer Immunotherapy and Autoimmunity, La Jolla Institute for ImmunologyDepartment of Biostatistics and Medical Informatics, University of Wisconsin-MadisonDepartment of Biostatistics and Medical Informatics, University of Wisconsin-MadisonWisconsin Institute for Discovery, University of Wisconsin-MadisonCenter for Cancer Immunotherapy and Autoimmunity, La Jolla Institute for ImmunologyDepartment of Pathology, Virginia Commonwealth UniversityAbstract Changes in the three-dimensional (3D) structure of the genome are an emerging hallmark of cancer. Cancer-associated copy number variants and single nucleotide polymorphisms promote rewiring of chromatin loops, disruption of topologically associating domains (TADs), active/inactive chromatin state switching, leading to oncogene expression and silencing of tumor suppressors. However, little is known about 3D changes during cancer progression to a chemotherapy-resistant state. We integrated chromatin conformation capture (Hi-C), RNA-seq, and whole-genome sequencing obtained from triple-negative breast cancer patient-derived xenograft primary tumors (UCD52) and carboplatin-resistant samples and found increased short-range (< 2 Mb) interactions, chromatin looping, formation of TAD, chromatin state switching into a more active state, and amplification of ATP-binding cassette transporters. Transcriptome changes suggested the role of long-noncoding RNAs in carboplatin resistance. Rewiring of the 3D genome was associated with TP53, TP63, BATF, FOS-JUN family of transcription factors and led to activation of aggressiveness-, metastasis- and other cancer-related pathways. Integrative analysis highlighted increased ribosome biogenesis and oxidative phosphorylation, suggesting the role of mitochondrial energy metabolism. Our results suggest that 3D genome remodeling may be a key mechanism underlying carboplatin resistance.https://doi.org/10.1038/s41598-023-32568-7 |
| spellingShingle | Mikhail G. Dozmorov Maggie A. Marshall Narmeen S. Rashid Jacqueline M. Grible Aaron Valentine Amy L. Olex Kavita Murthy Abhijit Chakraborty Joaquin Reyna Daniela Salgado Figueroa Laura Hinojosa-Gonzalez Erika Da-Inn Lee Brittany A. Baur Sushmita Roy Ferhat Ay J. Chuck Harrell Rewiring of the 3D genome during acquisition of carboplatin resistance in a triple-negative breast cancer patient-derived xenograft Scientific Reports |
| title | Rewiring of the 3D genome during acquisition of carboplatin resistance in a triple-negative breast cancer patient-derived xenograft |
| title_full | Rewiring of the 3D genome during acquisition of carboplatin resistance in a triple-negative breast cancer patient-derived xenograft |
| title_fullStr | Rewiring of the 3D genome during acquisition of carboplatin resistance in a triple-negative breast cancer patient-derived xenograft |
| title_full_unstemmed | Rewiring of the 3D genome during acquisition of carboplatin resistance in a triple-negative breast cancer patient-derived xenograft |
| title_short | Rewiring of the 3D genome during acquisition of carboplatin resistance in a triple-negative breast cancer patient-derived xenograft |
| title_sort | rewiring of the 3d genome during acquisition of carboplatin resistance in a triple negative breast cancer patient derived xenograft |
| url | https://doi.org/10.1038/s41598-023-32568-7 |
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