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

doi:10.1016/j.cell.2020.07.030

Large-Scale Topological Changes Restrain Malignant Progression in Colorectal Cancer

Cell. 2020 Sep 17;182(6):1474-1489.e23. doi: 10.1016/j.cell.2020.07.030. Epub 2020 Aug 24.

Authors

Sarah E Johnstone¹, Alejandro Reyes², Yifeng Qi³, Carmen Adriaens¹, Esmat Hegazi¹, Karin Pelka⁴, Jonathan H Chen¹, Luli S Zou², Yotam Drier⁵, Vivian Hecht⁶, Noam Shoresh⁶, Martin K Selig⁷, Caleb A Lareau⁸, Sowmya Iyer⁷, Son C Nguyen⁹, Eric F Joyce⁹, Nir Hacohen⁴, Rafael A Irizarry², Bin Zhang³, Martin J Aryee¹⁰, Bradley E Bernstein¹¹

Affiliations

¹ Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02129, USA.
² Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Department of Data Sciences, Dana Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard School of Public Health, Boston, MA 02215, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02129, USA.
⁵ The Lautenberg Center for Immunology and Cancer Research, The Hebrew University, Jerusalem, Israel.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
⁷ Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁸ Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02215, USA.
⁹ Department of Genetics, Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁰ Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02129, USA; Department of Biostatistics, Harvard School of Public Health, Boston, MA 02215, USA. Electronic address: aryee.martin@mgh.harvard.edu.
¹¹ Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02129, USA. Electronic address: bernstein.bradley@mgh.harvard.edu.

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.

Keywords: DNA methylation; chromatin; colon cancer; compartment; epigenetics; genome topology; nuclear architecture.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Division
Cellular Senescence / genetics
Chromatin / metabolism*
Chromatin Immunoprecipitation Sequencing
Chromosomes / genetics
Chromosomes / metabolism*
Cohort Studies
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / metabolism*
Colorectal Neoplasms / mortality
Colorectal Neoplasms / pathology
Computational Biology
DNA Methylation* / genetics
Epigenesis, Genetic*
Epigenomics
Gene Expression Regulation, Neoplastic / genetics*
HCT116 Cells
Humans
In Situ Hybridization, Fluorescence
Microscopy, Electron, Transmission
Molecular Dynamics Simulation
RNA-Seq
Spatial Analysis
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism

Substances

Chromatin
Tumor Suppressor Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding