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

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

Department of Immunology and Cancer Research

Research output: Contribution to journal › Article › peer-review

82 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 language	American English
Pages (from-to)	1474-1489.e23
Journal	Cell
Volume	182
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2020.07.030
State	Published - 17 Sep 2020

Bibliographical note

Funding Information:
We thank Ryanne Boursiquot for assistance with sequencing; Mohammed Miri for assistance with clinical samples; Elizabeth Gaskell, Volker Hovestadt, Christine Eyler and Ryan Corcoran, Angela Shih, and Omer Yilmaz for thoughtful discussions; and Leslie Gaffney for graphic support. S.E.J. is supported by NIH T32CA009216 . A.R. and R.A.I. are supported by NIH R01GM083084 and R01HG005220 . J.H.C. is supported by NIH 1T32CA207021-01 . M.J.A. is supported by a Broad Institute Merkin Fellowship. B.E.B. is the Bernard and Mildred Kayden Endowed MGH Research Institute Chair and an American Cancer Society Research Professor. This research was supported by the National Cancer Institute ( DP1CA216873 ) and the Starr Cancer Consortium . This paper is dedicated to the memory of Yaw Adu Kuffour.

Funding Information:
We thank Ryanne Boursiquot for assistance with sequencing; Mohammed Miri for assistance with clinical samples; Elizabeth Gaskell, Volker Hovestadt, Christine Eyler and Ryan Corcoran, Angela Shih, and Omer Yilmaz for thoughtful discussions; and Leslie Gaffney for graphic support. S.E.J. is supported by NIH T32CA009216. A.R. and R.A.I. are supported by NIH R01GM083084 and R01HG005220. J.H.C. is supported by NIH 1T32CA207021-01. M.J.A. is supported by a Broad Institute Merkin Fellowship. B.E.B. is the Bernard and Mildred Kayden Endowed MGH Research Institute Chair and an American Cancer Society Research Professor. This research was supported by the National Cancer Institute (DP1CA216873) and the Starr Cancer Consortium. This paper is dedicated to the memory of Yaw Adu Kuffour. Conception and Experimental Design, S.E.J. A.R. M.J.A. and B.E.B.; Methodology and Data Acquisition, S.E.J. A.R. C.A. E.H. K.P. J.H.C. and B.E.B.; Analysis and Interpretation of Data, S.E.J. A.R. Y.Q. C.A. L.S.Z. Y.D. V.H. N.S. M.K.S. C.L. S.I. S.C.N. E.F.J. N.H. R.A.I. B.Z. M.J.A. and B.E.B. Manuscript Writing and Revision, S.E.J. A.R. M.J.A. and B.E.B. N.H. is an equity holder of BioNTech and a consultant for Related Sciences. M.J.A. declares outside interest in Excelsior Genomics. B.E.B. declares outside interests in Fulcrum Therapeutics, 1CellBio, HiFiBio, Arsenal Biosciences, Cell Signaling Technologies, BioMillenia, and Nohla Therapeutics.

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

DNA methylation
chromatin
colon cancer
compartment
epigenetics
genome topology
nuclear architecture

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cell.2020.07.030

Cite this

Johnstone, S. E., Reyes, A., Qi, Y., Adriaens, C., Hegazi, E., Pelka, K., Chen, J. H., Zou, L. S., Drier, Y., Hecht, V., Shoresh, N., Selig, M. K., Lareau, C. A., Iyer, S., Nguyen, S. C., Joyce, E. F., Hacohen, N., Irizarry, R. A., Zhang, B., ... Bernstein, B. E. (2020). Large-Scale Topological Changes Restrain Malignant Progression in Colorectal Cancer. Cell, 182(6), 1474-1489.e23. https://doi.org/10.1016/j.cell.2020.07.030

@article{832299658b9d41f8ba5b8b04f4823da5,

title = "Large-Scale Topological Changes Restrain Malignant Progression in Colorectal Cancer",

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",

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

note = "Funding Information: We thank Ryanne Boursiquot for assistance with sequencing; Mohammed Miri for assistance with clinical samples; Elizabeth Gaskell, Volker Hovestadt, Christine Eyler and Ryan Corcoran, Angela Shih, and Omer Yilmaz for thoughtful discussions; and Leslie Gaffney for graphic support. S.E.J. is supported by NIH T32CA009216 . A.R. and R.A.I. are supported by NIH R01GM083084 and R01HG005220 . J.H.C. is supported by NIH 1T32CA207021-01 . M.J.A. is supported by a Broad Institute Merkin Fellowship. B.E.B. is the Bernard and Mildred Kayden Endowed MGH Research Institute Chair and an American Cancer Society Research Professor. This research was supported by the National Cancer Institute ( DP1CA216873 ) and the Starr Cancer Consortium . This paper is dedicated to the memory of Yaw Adu Kuffour. Funding Information: We thank Ryanne Boursiquot for assistance with sequencing; Mohammed Miri for assistance with clinical samples; Elizabeth Gaskell, Volker Hovestadt, Christine Eyler and Ryan Corcoran, Angela Shih, and Omer Yilmaz for thoughtful discussions; and Leslie Gaffney for graphic support. S.E.J. is supported by NIH T32CA009216. A.R. and R.A.I. are supported by NIH R01GM083084 and R01HG005220. J.H.C. is supported by NIH 1T32CA207021-01. M.J.A. is supported by a Broad Institute Merkin Fellowship. B.E.B. is the Bernard and Mildred Kayden Endowed MGH Research Institute Chair and an American Cancer Society Research Professor. This research was supported by the National Cancer Institute (DP1CA216873) and the Starr Cancer Consortium. This paper is dedicated to the memory of Yaw Adu Kuffour. Conception and Experimental Design, S.E.J. A.R. M.J.A. and B.E.B.; Methodology and Data Acquisition, S.E.J. A.R. C.A. E.H. K.P. J.H.C. and B.E.B.; Analysis and Interpretation of Data, S.E.J. A.R. Y.Q. C.A. L.S.Z. Y.D. V.H. N.S. M.K.S. C.L. S.I. S.C.N. E.F.J. N.H. R.A.I. B.Z. M.J.A. and B.E.B. Manuscript Writing and Revision, S.E.J. A.R. M.J.A. and B.E.B. N.H. is an equity holder of BioNTech and a consultant for Related Sciences. M.J.A. declares outside interest in Excelsior Genomics. B.E.B. declares outside interests in Fulcrum Therapeutics, 1CellBio, HiFiBio, Arsenal Biosciences, Cell Signaling Technologies, BioMillenia, and Nohla Therapeutics. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = sep,

day = "17",

doi = "10.1016/j.cell.2020.07.030",

language = "American English",

volume = "182",

pages = "1474--1489.e23",

journal = "Cell",

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Johnstone, SE, Reyes, A, Qi, Y, Adriaens, C, Hegazi, E, Pelka, K, Chen, JH, Zou, LS, Drier, Y, Hecht, V, Shoresh, N, Selig, MK, Lareau, CA, Iyer, S, Nguyen, SC, Joyce, EF, Hacohen, N, Irizarry, RA, Zhang, B, Aryee, MJ & Bernstein, BE 2020, 'Large-Scale Topological Changes Restrain Malignant Progression in Colorectal Cancer', Cell, vol. 182, no. 6, pp. 1474-1489.e23. https://doi.org/10.1016/j.cell.2020.07.030

TY - JOUR

T1 - Large-Scale Topological Changes Restrain Malignant Progression in Colorectal Cancer

AU - Johnstone, Sarah E.

AU - Reyes, Alejandro

AU - Qi, Yifeng

AU - Adriaens, Carmen

AU - Hegazi, Esmat

AU - Pelka, Karin

AU - Chen, Jonathan H.

AU - Zou, Luli S.

AU - Drier, Yotam

AU - Hecht, Vivian

AU - Shoresh, Noam

AU - Selig, Martin K.

AU - Lareau, Caleb A.

AU - Iyer, Sowmya

AU - Nguyen, Son C.

AU - Joyce, Eric F.

AU - Hacohen, Nir

AU - Irizarry, Rafael A.

AU - Zhang, Bin

AU - Aryee, Martin J.

AU - Bernstein, Bradley E.

N1 - Funding Information: We thank Ryanne Boursiquot for assistance with sequencing; Mohammed Miri for assistance with clinical samples; Elizabeth Gaskell, Volker Hovestadt, Christine Eyler and Ryan Corcoran, Angela Shih, and Omer Yilmaz for thoughtful discussions; and Leslie Gaffney for graphic support. S.E.J. is supported by NIH T32CA009216 . A.R. and R.A.I. are supported by NIH R01GM083084 and R01HG005220 . J.H.C. is supported by NIH 1T32CA207021-01 . M.J.A. is supported by a Broad Institute Merkin Fellowship. B.E.B. is the Bernard and Mildred Kayden Endowed MGH Research Institute Chair and an American Cancer Society Research Professor. This research was supported by the National Cancer Institute ( DP1CA216873 ) and the Starr Cancer Consortium . This paper is dedicated to the memory of Yaw Adu Kuffour. Funding Information: We thank Ryanne Boursiquot for assistance with sequencing; Mohammed Miri for assistance with clinical samples; Elizabeth Gaskell, Volker Hovestadt, Christine Eyler and Ryan Corcoran, Angela Shih, and Omer Yilmaz for thoughtful discussions; and Leslie Gaffney for graphic support. S.E.J. is supported by NIH T32CA009216. A.R. and R.A.I. are supported by NIH R01GM083084 and R01HG005220. J.H.C. is supported by NIH 1T32CA207021-01. M.J.A. is supported by a Broad Institute Merkin Fellowship. B.E.B. is the Bernard and Mildred Kayden Endowed MGH Research Institute Chair and an American Cancer Society Research Professor. This research was supported by the National Cancer Institute (DP1CA216873) and the Starr Cancer Consortium. This paper is dedicated to the memory of Yaw Adu Kuffour. Conception and Experimental Design, S.E.J. A.R. M.J.A. and B.E.B.; Methodology and Data Acquisition, S.E.J. A.R. C.A. E.H. K.P. J.H.C. and B.E.B.; Analysis and Interpretation of Data, S.E.J. A.R. Y.Q. C.A. L.S.Z. Y.D. V.H. N.S. M.K.S. C.L. S.I. S.C.N. E.F.J. N.H. R.A.I. B.Z. M.J.A. and B.E.B. Manuscript Writing and Revision, S.E.J. A.R. M.J.A. and B.E.B. N.H. is an equity holder of BioNTech and a consultant for Related Sciences. M.J.A. declares outside interest in Excelsior Genomics. B.E.B. declares outside interests in Fulcrum Therapeutics, 1CellBio, HiFiBio, Arsenal Biosciences, Cell Signaling Technologies, BioMillenia, and Nohla Therapeutics. Publisher Copyright: © 2020 Elsevier Inc.

PY - 2020/9/17

Y1 - 2020/9/17

N2 - 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.

AB - 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.

KW - DNA methylation

KW - chromatin

KW - colon cancer

KW - compartment

KW - epigenetics

KW - genome topology

KW - nuclear architecture

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U2 - 10.1016/j.cell.2020.07.030

DO - 10.1016/j.cell.2020.07.030

M3 - Article

C2 - 32841603

AN - SCOPUS:85090483924

SN - 0092-8674

VL - 182

SP - 1474-1489.e23

JO - Cell

JF - Cell

IS - 6

ER -

Large-Scale Topological Changes Restrain Malignant Progression in Colorectal Cancer

Abstract

Bibliographical note

Keywords

UN SDGs

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