Large-Scale Topological Changes Restrain Malignant Progression in Colorectal Cancer

Sarah E. Johnstone, Alejandro Reyes, Yifeng Qi, Carmen Adriaens, Esmat Hegazi, Karin Pelka, Jonathan H. Chen, Luli S. Zou, Yotam Drier, Vivian Hecht, Noam Shoresh, Martin K. Selig, Caleb A. Lareau, Sowmya Iyer, Son C. Nguyen, Eric F. Joyce, Nir Hacohen, Rafael A. Irizarry, Bin Zhang, Martin J. Aryee*Bradley E. Bernstein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

104 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)1474-1489.e23
JournalCell
Volume182
Issue number6
DOIs
StatePublished - 17 Sep 2020

Bibliographical note

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

  • DNA methylation
  • chromatin
  • colon cancer
  • compartment
  • epigenetics
  • genome topology
  • nuclear architecture

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