BORIS promotes chromatin regulatory interactions in treatment-resistant cancer cells

David N. Debruyne, Ruben Dries, Satyaki Sengupta, Davide Seruggia, Yang Gao, Bandana Sharma, Hao Huang, Lisa Moreau, Michael McLane, Daniel S. Day, Eugenio Marco, Ting Chen, Nathanael S. Gray, Kwok-Kin Wong, Stuart H. Orkin, Guo-Cheng Yuan, Richard A. Young and Rani E. George ()
Additional contact information
David N. Debruyne: Dana-Farber Cancer Institute
Ruben Dries: Dana-Farber Cancer Institute
Satyaki Sengupta: Dana-Farber Cancer Institute
Davide Seruggia: Dana-Farber Cancer Institute
Yang Gao: Dana-Farber Cancer Institute
Bandana Sharma: Dana-Farber Cancer Institute
Hao Huang: Dana-Farber Cancer Institute
Lisa Moreau: Dana-Farber Cancer Institute
Michael McLane: Dana-Farber Cancer Institute
Daniel S. Day: Whitehead Institute for Biomedical Research
Eugenio Marco: Dana-Farber Cancer Institute
Ting Chen: Dana-Farber Cancer Institute
Nathanael S. Gray: Dana-Farber Cancer Institute
Kwok-Kin Wong: New York University Langone Medical Center
Stuart H. Orkin: Dana-Farber Cancer Institute
Guo-Cheng Yuan: Dana-Farber Cancer Institute
Richard A. Young: Whitehead Institute for Biomedical Research
Rani E. George: Dana-Farber Cancer Institute

Nature, 2019, vol. 572, issue 7771, 676-680

Abstract: Abstract The CCCTC-binding factor (CTCF), which anchors DNA loops that organize the genome into structural domains, has a central role in gene control by facilitating or constraining interactions between genes and their regulatory elements1,2. In cancer cells, the disruption of CTCF binding at specific loci by somatic mutation3,4 or DNA hypermethylation5 results in the loss of loop anchors and consequent activation of oncogenes. By contrast, the germ-cell-specific paralogue of CTCF, BORIS (brother of the regulator of imprinted sites, also known as CTCFL)6, is overexpressed in several cancers7–9, but its contributions to the malignant phenotype remain unclear. Here we show that aberrant upregulation of BORIS promotes chromatin interactions in ALK-mutated, MYCN-amplified neuroblastoma10 cells that develop resistance to ALK inhibition. These cells are reprogrammed to a distinct phenotypic state during the acquisition of resistance, a process defined by the initial loss of MYCN expression followed by subsequent overexpression of BORIS and a concomitant switch in cellular dependence from MYCN to BORIS. The resultant BORIS-regulated alterations in chromatin looping lead to the formation of super-enhancers that drive the ectopic expression of a subset of proneural transcription factors that ultimately define the resistance phenotype. These results identify a previously unrecognized role of BORIS—to promote regulatory chromatin interactions that support specific cancer phenotypes.

Date: 2019
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DOI: 10.1038/s41586-019-1472-0

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