Format

Send to

Choose Destination
Nature. 2019 Aug;572(7771):676-680. doi: 10.1038/s41586-019-1472-0. Epub 2019 Aug 7.

BORIS promotes chromatin regulatory interactions in treatment-resistant cancer cells.

Debruyne DN1,2, Dries R1,2,3, Sengupta S1,2, Seruggia D1,4,5,6, Gao Y1,2, Sharma B1,2, Huang H1,2, Moreau L7, McLane M1,2, Day DS8,9, Marco E3,10, Chen T11, Gray NS12,13, Wong KK14, Orkin SH1,4,5,6, Yuan GC3,10, Young RA8,9, George RE15,16,17.

Author information

1
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
2
Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
3
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
4
Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
5
Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA.
6
Howard Hughes Medical Institute, Boston, MA, USA.
7
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
8
Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
9
MIT Department of Biology, Cambridge, MA, USA.
10
Department of Biostatistics, Harvard TC Chan School of Public Health, Boston, MA, USA.
11
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
12
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
13
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
14
Division of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.
15
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. rani_george@dfci.harvard.edu.
16
Department of Pediatrics, Harvard Medical School, Boston, MA, USA. rani_george@dfci.harvard.edu.
17
Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. rani_george@dfci.harvard.edu.

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.

PMID:
31391581
DOI:
10.1038/s41586-019-1472-0

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center