Cell
Volume 182, Issue 6, 17 September 2020, Pages 1474-1489.e23
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Article
Large-Scale Topological Changes Restrain Malignant Progression in Colorectal Cancer

https://doi.org/10.1016/j.cell.2020.07.030Get rights and content
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Highlights

  • Hierarchical layers of nuclear architecture are altered in colorectal tumors

  • An intermediate genome compartment is defined in primary tissues

  • Compartmental reorganization and hypomethylation occur in tumors and aging cells

  • Reorganization is associated with tumor-suppressive transcriptional programs

Summary

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.

Keywords

genome topology
chromatin
DNA methylation
colon cancer
epigenetics
nuclear architecture
compartment

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These authors contributed equally

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