Large-Scale Topological Changes Restrain Malignant Progression in Colorectal Cancer
SE Johnstone and A Reyes and YF Qi and C Adriaens and E Hegazi and K Pelka and JH Chen and LLS Zou and Y Drier and V Hecht and N Shoresh and MK Selig and CA Lareau and S Iyer and SC Nguyen and EF Joyce and N Hacohen and RA Irizarry and B Zhang and MJ Aryee and BE Bernstein, CELL, 182, 1474-+ (2020).
Widespread changes to DNA methylation and chromatin are well documented in cancer, but the fate of higher-order chromosomal structure remains obscure. Herewe 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.
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