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.

DNA 甲基化和染色质的广泛变化在癌症中得到了很好的记录，但高阶染色体结构的命运仍然模糊不清。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分区在肿瘤中受到严重损害。这种重组伴随着区室特异性低甲基化和染色质变化。此外，我们在肿瘤中重组的规范 A 和 B 隔室之间的界面处确定了一个隔室。值得注意的是，类似的变化在积累了过多分裂的非恶性细胞中也很明显。我们的分析表明，这些拓扑变化抑制干细胞和侵袭程序，同时诱导抗肿瘤免疫基因，因此可能抑制恶性进展。我们的研究结果对传统观点提出质疑，即肿瘤相关的表观基因组改变主要是致癌的。