Author:
Dozmorov Mikhail G.,Marshall Maggie A.,Rashid Narmeen S.,Grible Jacqueline M.,Valentine Aaron,Olex Amy L.,Murthy Kavita,Chakraborty Abhijit,Reyna Joaquin,Figueroa Daniela Salgado,Hinojosa-Gonzalez Laura,Da-Inn Lee Erika,Baur Brittany A.,Roy Sushmita,Ay Ferhat,Harrell J. Chuck
Abstract
AbstractChanges 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.
Funder
Pharmaceutical Research and Manufacturers of America Foundation
Blick Research Scholarship
National Institute of General Medical Sciences
National Cancer Institute
Susan G. Komen
Publisher
Springer Science and Business Media LLC
Cited by
1 articles.
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