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| Status |
Public on Apr 06, 2023 |
| Title |
Carboplatin resistance-associated changes in the 3D chromatin landscape of a triple-negative breast cancer Patient-Derived Xenograft [RNA-Seq] |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Changes in the three-dimensional (3D) structure of the genome are an emerging hallmark of cancer. However, little is known about the rewiring of the 3D chromatin landscape during cancer progression to a chemotherapy-resistant state. We utilized a patient-derived xenograft (PDX) mouse model of triple-negative breast cancer (UCD52) to characterize changes in the 3D structure between the primary tumor and carboplatin-resistant state. Systematic integration of matched chromatin conformation capture (Hi-C), RNA-seq, and whole-genome sequencing data revealed a widespread increase in short-range (<2Mb) interactions with the corresponding increase in chromatin looping and topologically associating domain (TAD) formation, chromatin state switching into a more active state, large-scale deletions, amplification of ATP-binding cassette (ABC) transporters and nearly complete shutdown of drug metabolism pathways. Rewiring of the 3D genome was associated with TP53, TP63, BATF, FOS-JUN family of transcription factors and led to activation of many aggressiveness-, metastasis- and other cancer-related pathways. Transcriptome changes suggest the role of downregulated protein-coding genes and upregulated long-noncoding RNAs in drug resistance. Integrative analysis confirmed increased ribosome biogenesis and oxidative phosphorylation, suggesting the role of mitochondrial metabolic processes. Our results highlight that 3D genome remodeling may be a key mechanism underlying drug resistance.
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| Overall design |
RNA-sequencing analysis performed on three replicates for each of the two phenotypes (primary tumor and carboplatin-resistant state).
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| Contributor(s) |
Dozmorov MG, Marshall MA, Rashid N, Grible J, Olex AL, Murthy K, Chakraborty A, Reyna J, Salgado Figueroa D, Da-Inn Lee E, Baur B, Roy S, Ay F, Harrell C |
| Citation(s) |
37012431, 37160896 |
| Submission date |
Apr 25, 2022 |
| Last update date |
Aug 04, 2023 |
| Contact name |
Mikhail Dozmorov |
| E-mail(s) |
mdozmorov@vcu.edu
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| Organization name |
Virginia Commonwealth University
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| Department |
Biostatistics
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| Street address |
830 E Main St
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| City |
Richmond |
| State/province |
VA |
| ZIP/Postal code |
23298 |
| Country |
USA |
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| Platforms (1) |
| GPL22245 |
Illumina HiSeq 2500 (Homo sapiens; Mus musculus) |
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| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE201435 |
Carboplatin resistance-associated changes in the 3D chromatin landscape of a triple-negative breast cancer Patient-Derived Xenograft |
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| Relations |
| BioProject |
PRJNA831784 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE201434_RAW.tar |
22.5 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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