CELL:颠覆传统观念,染色质拓扑变化可抑制结直肠癌的恶性进展

2020-08-25 haibei MedSci原创

最近,研究人员在CELL杂志发文,将结肠肿瘤和正常结肠的拓扑图与表观遗传学、转录和成像数据整合在一起,以表征染色质环、拓扑相关域和大规模隔室的改变。

一个多世纪以来,病理学家已经观察到癌细胞核的形状、大小和染色质质地的变化。核特征有助于确定癌症的亚型和等级,对预后和治疗有重要的影响。然而,尽管它们具有诊断和临床的重要性,但我们对于这些与癌症相关的形态学变化的分子基础仍然知之甚少。

分子和遗传学研究已经记录了人类肿瘤中广泛的表观遗传学缺陷,包括染色质调节剂突变、DNA甲基化变化和增强子景观的改变。一些癌症中还蕴藏着调控高阶染色体结构("基因组拓扑")的蛋白质的突变,包括CTCF和cohesin亚单位。局部拓扑学改变在特定背景下驱动致癌转录程序。尽管如此,至今为止,人类肿瘤中的基因组拓扑和核组织在很大程度上是未知的。

最近,研究人员在CELL杂志发文,将结肠肿瘤和正常结肠的拓扑图与表观遗传学、转录和成像数据整合在一起,以表征染色质环、拓扑相关域和大规模隔室的改变。

为了了解核结构在癌症中是如何改变的,研究人员剖析了原发性结肠肿瘤、正常结肠和结肠癌细胞系中的基因组拓扑以及DNA甲基化、染色质修饰和CTCF。该研究的临床队列包括26个肿瘤和7个正常结肠组织样本;体外模型包括结肠癌细胞系(HCT116,SW480,RKO和LS-174T),一个来自正常结肠的系(FHC),和原代成纤维细胞(WI-38)。该研究的完整数据集包括175个库和280亿个测序读数,用于Hi-C、HiChIP、双硫酸盐测序、染色质免疫共沉淀测序(ChIP-seq)和RNA测序(RNA-seq)。

研究人员发现,在肿瘤中,开放和封闭的基因组隔室的空间分区受到了深刻的损害。这种重组伴随着隔室特异性的低甲基化和染色质变化。此外,研究人员还在肿瘤中发现了一个位于常规的A和B区室之间的界面上的区室被重组。

值得注意的是,在多次分裂的非恶性细胞中也有类似的转变。研究人员的分析还表明,这些拓扑变化在诱导抗肿瘤免疫基因的同时,也抑制了干细胞和入侵程序,因此可能抑制了恶性肿瘤的进展。

总之,以往人们认为肿瘤相关的表观基因组改变主要是致癌的,本研究对此传统观念提出了质疑。

 

原始出处:

Sarah E. Johnstone et al. Large-Scale Topological Changes Restrain Malignant Progression in Colorectal Cancer. CELL (2020). DOI:https://doi.org/10.1016/j.cell.2020.07.030

 

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    2020-09-08 爆笑小医
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    2020-08-30 ms3000000449926787

    牛逼的研究!

    0

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    2020-08-27 ms4000002082197205

    好资料

    0

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    2020-08-27 ms3000000956234844

    学习了

    0

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    2020-08-27 ms7000000689223974

    很好很详细,谢谢分享

    0

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