Super-Enhancer Redistribution as a Mechanism of Broad Gene Dysregulation in Repeatedly Drug-Treated Cancer Cells
| Autor: | Soohwan Oh, Feng Yang, Ranveer Singh Jayani, Daria Merkurjev, Wubin Ma, Chunyu Jin, Qi Ma, Ivan Garcia-Bassets, Stephanie Allen, Dong Wang, Carlos Mackintosh, Sreejith J Nair, Angels Almenar-Queralt |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Transcription Genetic Regulator Antineoplastic Agents Biology General Biochemistry Genetics and Molecular Biology Transcriptome 03 medical and health sciences 0302 clinical medicine Super-enhancer Neoplasms medicine CRISPR Humans Ribosome profiling lcsh:QH301-705.5 Cisplatin Chromatin 030104 developmental biology Enhancer Elements Genetic lcsh:Biology (General) Cancer cell Cancer research 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Cell Reports, Vol 31, Iss 3, Pp-(2020) |
| ISSN: | 2211-1247 |
| Popis: | Summary: Cisplatin is an antineoplastic drug administered at suboptimal and intermittent doses to avoid life-threatening effects. Although this regimen shortly improves symptoms in the short term, it also leads to more malignant disease in the long term. We describe a multilayered analysis ranging from chromatin to translation—integrating chromatin immunoprecipitation sequencing (ChIP-seq), global run-on sequencing (GRO-seq), RNA sequencing (RNA-seq), and ribosome profiling—to understand how cisplatin confers (pre)malignant features by using a well-established ovarian cancer model of cisplatin exposure. This approach allows us to segregate the human transcriptome into gene modules representing distinct regulatory principles and to characterize that the most cisplatin-disrupted modules are associated with underlying events of super-enhancer plasticity. These events arise when cancer cells initiate without ultimately ending the program of drug-stimulated death. Using a PageRank-based algorithm, we predict super-enhancer regulator ISL1 as a driver of this plasticity and validate this prediction by using CRISPR/dCas9-KRAB inhibition (CRISPRi) and CRISPR/dCas9-VP64 activation (CRISPRa) tools. Together, we propose that cisplatin reprograms cancer cells when inducing them to undergo near-to-death experiences. : Ovarian tumors acquire new phenotypic features when exposed to anticancer therapy, which helps them endure the struggle for survival and increase malignancy. Using a six-layered multiomic approach, Ma et al. find that selective super-enhancer redistribution is a major driver of the acquisition of new phenotypic features. Keywords: multi-omic approach, gene dysregulation, super-enhancer, cisplatin, drug resistance, ovarian cancer, GRO-seq, ribosome profiling, Seurat, PageRank |
| Databáze: | OpenAIRE |
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