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BORIS promotes chromatin regulatory interactions in treatment-resistant cancer cells

机译：BORIS促进抗治疗性癌细胞中的染色质调节相互作用

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摘要

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 elements(1,2). In cancer cells, the disruption of CTCF binding at specific loci by somatic mutation(3,4) or DNA hypermethylation(5) 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 cancers(7-9), 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 neuroblastoma(10) 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.
机译：CCCTC结合因子（CTCF）锚定了将基因组组织成结构域的DNA环，通过促进或限制基因与其调控元件之间的相互作用来在基因控制中发挥核心作用（1,2）。在癌细胞中，体细胞突变（3,4）或DNA超甲基化（5）破坏特定基因座处的CTCF结合，导致环锚的丧失和致癌基因的激活。相比之下，CTCF的生殖细胞特异性旁系同源物BORIS（印迹部位调节剂的兄弟，也称为CTCFL）（6）在几种癌症中过表达（7-9），但其对恶性表型的贡献仍不清楚。在这里，我们显示BORIS的异常上调促进ALK突变的，MYCN扩增的神经母细胞瘤（10）细胞中对ALK抑制产生抗性的染色质相互作用。这些细胞在获得抗药性的过程中被重新编程为独特的表型状态，这一过程由最初的MYCN表达丧失，随后的BORIS过表达和随之而来的细胞依赖性从MYCN到BORIS的转换所定义。由此产生的BORIS调节的染色质环的变化导致形成超级增强子，这些超级增强子会驱动最终定义抗性表型的proneural转录因子子集的异位表达。这些结果确定了BORIS以前无法识别的作用，以促进支持特定癌症表型的调节染色质相互作用。

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  • 来源
    《Nature》 |2019年第7771期|676-680|共5页
  • 作者

    Debruyne David N.; Dries Ruben; Sengupta Satyaki; Seruggia Davide; Gao Yang; Sharma Bandana; Huang Hao; Moreau Lisa; McLane Michael; Day Daniel S.; Marco Eugenio; Chen Ting; Gray Nathanael S.; Wong Kwok-Kin; Orkin Stuart H.; Yuan Guo-Cheng; Young Richard A.; George Rani E.;

  • 作者单位

    Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA|Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA|Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA|Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA|Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA|Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA|Harvard Med Sch, Harvard Stem Cell Inst, Boston, MA 02115 USA|Howard Hughes Med Inst, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA|Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA|Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA|Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA|Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA;

    Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA|MIT, Dept Biol, Cambridge, MA USA;

    Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA|Harvard TC Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA|Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA;

    NYU, Langone Med Ctr, Laura & Isaac Perlmutter Canc Ctr, Div Hematol & Med Oncol, New York, NY USA;

    Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA|Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA|Harvard Med Sch, Harvard Stem Cell Inst, Boston, MA 02115 USA|Howard Hughes Med Inst, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA|Harvard TC Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA;

    Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA|MIT, Dept Biol, Cambridge, MA USA;

    Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA|Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA|Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA;

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