Large-Scale Topological Changes Restrain Malignant Progression in Colorectal Cancer.
Large-Scale Topological Changes Restrain Malignant Progression in Colorectal Cancer.
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DOI：
10.1016/j.cell.2020.07.030
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发表时间：
2020-09-17
期刊：
影响因子：
64.5
通讯作者：
Bernstein BE
中科院分区：
文献类型：
--
作者：
Johnstone SE;Reyes A;Qi Y;Adriaens C;Hegazi E;Pelka K;Chen JH;Zou LS;Drier Y;Hecht V;Shoresh N;Selig MK;Lareau CA;Iyer S;Nguyen SC;Joyce EF;Hacohen N;Irizarry RA;Zhang B;Aryee MJ;Bernstein BE
DNA 甲基化和染色质的广泛变化在癌症中已有详细记录，但高阶染色体结构的命运仍然不清楚。在这里，我们将结肠肿瘤和正常结肠的拓扑图与表观遗传、转录和成像数据相结合，以表征染色质环、拓扑相关结构域和大规模区室的改变。我们发现开放和封闭基因组区室的空间划分在肿瘤中受到严重损害。这种重组伴随着区室特异性的低甲基化和染色质变化。此外，我们在肿瘤中重组的典型 A 和 B 区室之间的界面处发现了一个区室。值得注意的是，在积累了过度分裂的非恶性细胞中，类似的变化也很明显。我们的分析表明，这些拓扑变化抑制干性和侵袭程序，同时诱导抗肿瘤免疫基因，因此可能抑制恶性进展。我们的发现对肿瘤相关表观基因组改变主要是致癌的传统观点提出了质疑。对结直肠肿瘤的基因组拓扑、表观遗传和转录特征的综合分析强调了与肿瘤抑制而非致癌转录结果相关的实质性基因组区室重组。
Widespread changes to DNA methylation and chromatin are well documented in cancer, but the fate of higher-order chromosomal structure remains obscure. Here we integrated topological maps for colon tumors and normal colons with epigenetic, transcriptional, and imaging data to characterize alterations to chromatin loops, topologically associated domains, and large-scale compartments. We found that spatial partitioning of the open and closed genome compartments is profoundly compromised in tumors. This reorganization is accompanied by compartment-specific hypomethylation and chromatin changes. Additionally, we identify a compartment at the interface between the canonical A and B compartments that is reorganized in tumors. Remarkably, similar shifts were evident in non-malignant cells that have accumulated excess divisions. Our analyses suggest that these topological changes repress stemness and invasion programs while inducing anti-tumor immunity genes and may therefore restrain malignant progression. Our findings call into question the conventional view that tumor-associated epigenomic alterations are primarily oncogenic. Integrated analyses of genome topological, epigenetic, and transcriptional features of colorectal tumors highlight substantial genome compartmental reorganization associated with tumor-suppressive rather than oncogenic transcriptional outcomes.
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影响因子：
12.3
作者：
Fortin JP;Hansen KD
通讯作者：
Hansen KD
影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
影响因子：
64.8
作者：
Dixon JR;Jung I;Selvaraj S;Shen Y;Antosiewicz-Bourget JE;Lee AY;Ye Z;Kim A;Rajagopal N;Xie W;Diao Y;Liang J;Zhao H;Lobanenkov VV;Ecker JR;Thomson JA;Ren B
通讯作者：
Ren B
影响因子：
64.8
作者：
Falk, Martin;Feodorova, Yana;Mirny, Leonid A.
通讯作者：
Mirny, Leonid A.
使用 cLoops 准确循环调用 3D 基因组数据
影响因子：
5.8
作者：
Cao, Yaqiang;Chen, Zhaoxiong;Han, Jing-Dong J.
通讯作者：
Han, Jing-Dong J.