BORIS Promotes Chromatin Regulatory Interactions in Treatment-Resistant Cancer Cells
Young, Richard A.
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CitationDebruyne, David N., 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. 2019. BORIS Promotes Chromatin Regulatory Interactions in Treatment-resistant Cancer Cells. Nature 572, no. 7771: 676-680.
AbstractThe CCCTC-binding factor (CTCF), which anchors DNA loops that organize the genome into structural domains, plays a central role in gene control by facilitating or constraining interactions between genes and their regulatory elements. In cancer cells the disruption of CTCF binding at specific loci through somatic mutation or DNA hypermethylation5 results in the loss of loop anchors and consequent activation of oncogenes. By contrast, the germ cell-specific paralog of CTCF, BORIS (Brother of the Regulator of Imprinted Sites), is overexpressed in multiple cancers, but its contributions to the malignant phenotype remain unclear. Here we show that aberrant upregulation of BORIS promotes novel chromatin interactions in ALK-mutated, MYCN-amplified neuroblastoma cells rendered resistant 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 new 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 engender regulatory chromatin interactions that support specific cancer phenotypes.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42219239
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