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BORIS promotes chromatin regulatory interactions in treatment-resistant cancer cells

机译：鲍里斯促进治疗抗癌细胞中的染色质调节性相互作用

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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：将组织基因组组织成结构结构域的DNA结合因子（CTCF），其通过促进或约束基因与其调节元件（1,2）之间的相互作用，在基因对中具有核心作用。在癌细胞中，通过体细胞突变（3,4）或DNA高甲基化（5）在特定基因座上破坏CTCF结合（5）导致环锚的丧失并随后癌基因的活化。相比之下，CTCF的细胞特异性常规阶尿蛋白，鲍里斯（印迹位点调节剂的兄弟，也称为CTCFL）（6）在几种癌症（7-9）中过表达，但其对恶性表型的贡献仍然不清楚。在这里，我们表明鲍里斯的异常上调促进了染色蛋白相互作用，其产生了对ALK抑制抗性的抗性的染色体相互作用。在获取抗性期间，将这些细胞重新编程为不同的表型状态，该方法由MyCN表达的初始损失而定义，然后鲍里斯的过度表达和伴随从MyCN到鲍里斯的细胞依赖性的伴随开关。染色质循环中所得的硼砂调节改变导致超强增强剂的形成，其驱动最终定义抗性表型的散文转录因子子集的异位表达。这些结果确定了鲍里斯 - 促进支持特异性癌症表型的调节染色质相互作用的先前未被识别的作用。

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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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