Large-Scale Topological Changes Restrain Malignant Progression in Colorectal Cancer

• Published in: Cell 2020-09, Vol.182 (6), p.1474-1489.e23
• Main Authors: Johnstone, Sarah E., Reyes, Alejandro, Qi, Yifeng, Adriaens, Carmen, Hegazi, Esmat, Pelka, Karin, Chen, Jonathan H., Zou, Luli S., Drier, Yotam, Hecht, Vivian, Shoresh, Noam, Selig, Martin K., Lareau, Caleb A., Iyer, Sowmya, Nguyen, Son C., Joyce, Eric F., Hacohen, Nir, Irizarry, Rafael A., Zhang, Bin, Aryee, Martin J., Bernstein, Bradley E.
• Format: Article
• Language: English
• Subjects: Cell Division; Cellular Senescence - genetics; chromatin; Chromatin - metabolism; Chromatin Immunoprecipitation Sequencing; Chromosomes - genetics; Chromosomes - metabolism; Cohort Studies; colon cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; compartment; Computational Biology; DNA methylation; DNA Methylation - genetics; Epigenesis, Genetic; epigenetics; Epigenomics; Gene Expression Regulation, Neoplastic - genetics; genome topology; HCT116 Cells; Humans; In Situ Hybridization, Fluorescence; Microscopy, Electron, Transmission; Molecular Dynamics Simulation; nuclear architecture; RNA-Seq; Spatial Analysis; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2020.07.030

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. [Display omitted] •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 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.