Stratification of TAD boundaries reveals preferential insulation of super-enhancers by strong boundaries

Yixiao Gong; Charalampos Lazaris; Theodore Sakellaropoulos; Aurelie Lozano; Prabhanjan Kambadur; Panagiotis Ntziachristos; Iannis Aifantis; Aristotelis Tsirigos

doi:10.1038/s41467-018-03017-1

Stratification of TAD boundaries reveals preferential insulation of super-enhancers by strong boundaries

Yixiao Gong, Charalampos Lazaris, Theodore Sakellaropoulos, Aurelie Lozano, Prabhanjan Kambadur, Panagiotis Ntziachristos, Iannis Aifantis^*, Aristotelis Tsirigos

^*Corresponding author for this work

Biochemistry and Molecular Genetics

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

99 Scopus citations

Abstract

The metazoan genome is compartmentalized in areas of highly interacting chromatin known as topologically associating domains (TADs). TADs are demarcated by boundaries mostly conserved across cell types and even across species. However, a genome-wide characterization of TAD boundary strength in mammals is still lacking. In this study, we first use fused two-dimensional lasso as a machine learning method to improve Hi-C contact matrix reproducibility, and, subsequently, we categorize TAD boundaries based on their insulation score. We demonstrate that higher TAD boundary insulation scores are associated with elevated CTCF levels and that they may differ across cell types. Intriguingly, we observe that super-enhancers are preferentially insulated by strong boundaries. Furthermore, we demonstrate that strong TAD boundaries and super-enhancer elements are frequently co-duplicated in cancer patients. Taken together, our findings suggest that super-enhancers insulated by strong TAD boundaries may be exploited, as a functional unit, by cancer cells to promote oncogenesis.

Original language	English (US)
Article number	542
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-03017-1
State	Published - Dec 1 2018

Funding

We would like to thank all members of the Tsirigos and Aifantis Laboratories for critical evaluation of the manuscript, and Andreas Kloetgen who provided guidance on identifying specific interactions at fine resolutions. We would like to thank the Applied Bioinformatics Laboratories (ABL) at the NYU School of Medicine for providing bioinformatics support and helping with the analysis and interpretation of the data. This work has used computing resources at the NYU High Performance Computing Facility (HPCF). We also thank the Genome Technology Center (GTC) for expert library preparation and sequencing, and the Applied Bioinformatics Laboratories (ABL) for bioinformatics support. GTC and ABL are Shared Resources partially supported by the Cancer Center Support Grant, P30CA016087, at the Laura and Isaac Perlmutter Cancer Center. The study was supported by the American Cancer Society (RSG-15-189-01-RMC to A.T.), a Leukemia and Lymphoma Society New Idea Award (8007-17 to A.T.), and by NCI funding (R01CA169784, R01CA194923, R01CA216421 to I.A.).

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

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

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10.1038/s41467-018-03017-1

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title = "Stratification of TAD boundaries reveals preferential insulation of super-enhancers by strong boundaries",

abstract = "The metazoan genome is compartmentalized in areas of highly interacting chromatin known as topologically associating domains (TADs). TADs are demarcated by boundaries mostly conserved across cell types and even across species. However, a genome-wide characterization of TAD boundary strength in mammals is still lacking. In this study, we first use fused two-dimensional lasso as a machine learning method to improve Hi-C contact matrix reproducibility, and, subsequently, we categorize TAD boundaries based on their insulation score. We demonstrate that higher TAD boundary insulation scores are associated with elevated CTCF levels and that they may differ across cell types. Intriguingly, we observe that super-enhancers are preferentially insulated by strong boundaries. Furthermore, we demonstrate that strong TAD boundaries and super-enhancer elements are frequently co-duplicated in cancer patients. Taken together, our findings suggest that super-enhancers insulated by strong TAD boundaries may be exploited, as a functional unit, by cancer cells to promote oncogenesis.",

author = "Yixiao Gong and Charalampos Lazaris and Theodore Sakellaropoulos and Aurelie Lozano and Prabhanjan Kambadur and Panagiotis Ntziachristos and Iannis Aifantis and Aristotelis Tsirigos",

note = "Funding Information: We would like to thank all members of the Tsirigos and Aifantis Laboratories for critical evaluation of the manuscript, and Andreas Kloetgen who provided guidance on identifying specific interactions at fine resolutions. We would like to thank the Applied Bioinformatics Laboratories (ABL) at the NYU School of Medicine for providing bioinformatics support and helping with the analysis and interpretation of the data. This work has used computing resources at the NYU High Performance Computing Facility (HPCF). We also thank the Genome Technology Center (GTC) for expert library preparation and sequencing, and the Applied Bioinformatics Laboratories (ABL) for bioinformatics support. GTC and ABL are Shared Resources partially supported by the Cancer Center Support Grant, P30CA016087, at the Laura and Isaac Perlmutter Cancer Center. The study was supported by the American Cancer Society (RSG-15-189-01-RMC to A.T.), a Leukemia and Lymphoma Society New Idea Award (8007-17 to A.T.), and by NCI funding (R01CA169784, R01CA194923, R01CA216421 to I.A.). Publisher Copyright: {\textcopyright} 2018 The Author(s).",

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AU - Lazaris, Charalampos

AU - Sakellaropoulos, Theodore

AU - Lozano, Aurelie

AU - Kambadur, Prabhanjan

AU - Ntziachristos, Panagiotis

AU - Aifantis, Iannis

AU - Tsirigos, Aristotelis

N1 - Funding Information: We would like to thank all members of the Tsirigos and Aifantis Laboratories for critical evaluation of the manuscript, and Andreas Kloetgen who provided guidance on identifying specific interactions at fine resolutions. We would like to thank the Applied Bioinformatics Laboratories (ABL) at the NYU School of Medicine for providing bioinformatics support and helping with the analysis and interpretation of the data. This work has used computing resources at the NYU High Performance Computing Facility (HPCF). We also thank the Genome Technology Center (GTC) for expert library preparation and sequencing, and the Applied Bioinformatics Laboratories (ABL) for bioinformatics support. GTC and ABL are Shared Resources partially supported by the Cancer Center Support Grant, P30CA016087, at the Laura and Isaac Perlmutter Cancer Center. The study was supported by the American Cancer Society (RSG-15-189-01-RMC to A.T.), a Leukemia and Lymphoma Society New Idea Award (8007-17 to A.T.), and by NCI funding (R01CA169784, R01CA194923, R01CA216421 to I.A.). Publisher Copyright: © 2018 The Author(s).

PY - 2018/12/1

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N2 - The metazoan genome is compartmentalized in areas of highly interacting chromatin known as topologically associating domains (TADs). TADs are demarcated by boundaries mostly conserved across cell types and even across species. However, a genome-wide characterization of TAD boundary strength in mammals is still lacking. In this study, we first use fused two-dimensional lasso as a machine learning method to improve Hi-C contact matrix reproducibility, and, subsequently, we categorize TAD boundaries based on their insulation score. We demonstrate that higher TAD boundary insulation scores are associated with elevated CTCF levels and that they may differ across cell types. Intriguingly, we observe that super-enhancers are preferentially insulated by strong boundaries. Furthermore, we demonstrate that strong TAD boundaries and super-enhancer elements are frequently co-duplicated in cancer patients. Taken together, our findings suggest that super-enhancers insulated by strong TAD boundaries may be exploited, as a functional unit, by cancer cells to promote oncogenesis.

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Stratification of TAD boundaries reveals preferential insulation of super-enhancers by strong boundaries

Abstract

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ASJC Scopus subject areas

UN SDGs

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