美国丹娜-法伯癌症研究所Rani E. George课题组发现在治疗抵抗的癌细胞中，CCCTC结合因子（CTCF）的生殖细胞特异性旁系同源物BORIS（brother of the regulator of imprinted sites，也称为CTCFL）促进染色质调控性相互作用。该研究2019年8月29日发表于《自然》。

研究人员发现在ALK突变、MYCN扩增的神经母细胞瘤细胞中，BORIS的异常上调促进染色质相互作用，从而产生对ALK抑制的抗性。在获得抗性期间，这些细胞被重编程为不同的表型状态，在该过程中MYCN的表达丧失并随后出现BORIS的过表达，此外还伴随从MYCN到BORIS的细胞依赖性的转换。由此产生的BORIS调节的染色质环化改变导致超级增强子的形成，其驱动一类颈板转录因子的异位表达，最终产生了抗性表型。这些结果确定了先前未被认识到的BORIS作用，即促进支持特定癌症表型的调节性染色质相互作用。

据介绍，CTCF通过锚定DNA环化将基因组组织成结构域，从而促进或限制基因与其调控元件之间的相互作用，并在基因控制中发挥了核心作用。在癌细胞中，通过体细胞突变或DNA高甲基化能够破坏CTCF在特定基因座处的结合导致环-锚的丧失和随后的致癌基因的激活。相比之下，BORIS在几种癌症中过表达，但其对恶性表型的贡献仍不清楚。

附：英文原文

Title: BORIS promotes chromatin regulatory interactions in treatment-resistant cancer cells

Author: 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, Rani E. George

Issue&Volume: Volume 572 Issue 7771

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 cancers7,8,9, 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.

DOI: 10.1038/s41586-019-1472-0

Source:https://www.nature.com/articles/s41586-019-1472-0