Three-dimensional chromatin landscapes in T cell acute lymphoblastic leukemia

Andreas Kloetgen; Palaniraja Thandapani; Panagiotis Ntziachristos; Yohana Ghebrechristos; Sofia Nomikou; Charalampos Lazaris; Xufeng Chen; Hai Hu; Sofia Bakogianni; Jingjing Wang; Yi Fu; Francesco Boccalatte; Hua Zhong; Elisabeth Paietta; Thomas Trimarchi; Yixing Zhu; Pieter Van Vlierberghe; Giorgio G. Inghirami; Timothee Lionnet; Iannis Aifantis; Aristotelis Tsirigos

doi:10.1038/s41588-020-0602-9

Three-dimensional chromatin landscapes in T cell acute lymphoblastic leukemia

Andreas Kloetgen, Palaniraja Thandapani, Panagiotis Ntziachristos, Yohana Ghebrechristos, Sofia Nomikou, Charalampos Lazaris, Xufeng Chen, Hai Hu, Sofia Bakogianni, Jingjing Wang, Yi Fu, Francesco Boccalatte, Hua Zhong, Elisabeth Paietta, Thomas Trimarchi, Yixing Zhu, Pieter Van Vlierberghe, Giorgio G. Inghirami, Timothee Lionnet, Iannis Aifantis^*Aristotelis Tsirigos

^*Corresponding author for this work

Biochemistry and Molecular Genetics

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

126 Scopus citations

Abstract

Differences in three-dimensional (3D) chromatin architecture can influence the integrity of topologically associating domains (TADs) and rewire specific enhancer–promoter interactions, impacting gene expression and leading to human disease. Here we investigate the 3D chromatin architecture in T cell acute lymphoblastic leukemia (T-ALL) by using primary human leukemia specimens and examine the dynamic responses of this architecture to pharmacological agents. Systematic integration of matched in situ Hi-C, RNA-seq and CTCF ChIP–seq datasets revealed widespread differences in intra-TAD chromatin interactions and TAD boundary insulation in T-ALL. Our studies identify and focus on a TAD ‘fusion’ event associated with absence of CTCF-mediated insulation, enabling direct interactions between the MYC promoter and a distal super-enhancer. Moreover, our data also demonstrate that small-molecule inhibitors targeting either oncogenic signal transduction or epigenetic regulation can alter specific 3D interactions found in leukemia. Overall, our study highlights the impact, complexity and dynamic nature of 3D chromatin architecture in human acute leukemia.

Original language	English (US)
Pages (from-to)	388-400
Number of pages	13
Journal	Nature Genetics
Volume	52
Issue number	4
DOIs	https://doi.org/10.1038/s41588-020-0602-9
State	Published - Apr 1 2020

Funding

We thank all members of the Aifantis and Tsirigos laboratories for discussions throughout this project; A. Heguy and the NYU Genome Technology Center (supported in part by National Institutes of Health (NIH)/National Cancer Institute (NCI) grant P30CA016087-30) for expertise with sequencing experiments; the NYU Flow Cytometry facility for expert cell sorting; the Applied Bioinformatics Laboratory for computational assistance; and Genewiz for expertise with sequencing experiments. This work has used computing resources at the High-Performance Computing Facility at the NYU Medical Center. We would also like to acknowledge B. Ren and A. Schmitt for their support on the Hi-C experiments. I.A. is supported by the NCI/NIH (1P01CA229086, 1R01CA228135, R01CA216421, R01CA202025, R01CA133379, R01CA149655 and 1R01CA194923), Alex’s Lemonade Stand Cancer Research Foundation, the Chemotherapy Foundation, the Leukemia and Lymphoma Society and the NYSTEM program of the New York State Health Department. A.T. is supported by the American Cancer Society (RSG-15-189-01-RMC), the NCI/NIH (1P01CA229086), the Leukemia and Lymphoma Society and St. Baldrick’s Foundation. P.T. was previously supported by an AACR Incyte Corporation Leukemia Research Fellowship and is currently supported by a Young Investigator Grant from Alex’s Lemonade Stand Cancer Research Foundation. P.N. was supported by the NCI (R00CA188293), the American Society of Hematology, the Zell Foundation, the H Foundation and a grant (U54CA193419) from the NCI and the Chicago Region Physical Sciences–Oncology Center (CR-PSOC). P.V.V. was supported by a European Research Council Starting Grant (639784). T.L. is supported by the National Institute of General Medical Sciences (NIGMS)/NIH (R01GM127538). F.B. is supported by a Young Investigator Grant from Alex’s Lemonade Stand Cancer Research Foundation. S.N. is supported by the Onassis Foundation (scholarship ID F ZP 036-1/2019-2020).

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Genetics

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10.1038/s41588-020-0602-9

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Kloetgen, A., Thandapani, P., Ntziachristos, P., Ghebrechristos, Y., Nomikou, S., Lazaris, C., Chen, X., Hu, H., Bakogianni, S., Wang, J., Fu, Y., Boccalatte, F., Zhong, H., Paietta, E., Trimarchi, T., Zhu, Y., Van Vlierberghe, P., Inghirami, G. G., Lionnet, T., ... Tsirigos, A. (2020). Three-dimensional chromatin landscapes in T cell acute lymphoblastic leukemia. Nature Genetics, 52(4), 388-400. https://doi.org/10.1038/s41588-020-0602-9

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title = "Three-dimensional chromatin landscapes in T cell acute lymphoblastic leukemia",

abstract = "Differences in three-dimensional (3D) chromatin architecture can influence the integrity of topologically associating domains (TADs) and rewire specific enhancer–promoter interactions, impacting gene expression and leading to human disease. Here we investigate the 3D chromatin architecture in T cell acute lymphoblastic leukemia (T-ALL) by using primary human leukemia specimens and examine the dynamic responses of this architecture to pharmacological agents. Systematic integration of matched in situ Hi-C, RNA-seq and CTCF ChIP–seq datasets revealed widespread differences in intra-TAD chromatin interactions and TAD boundary insulation in T-ALL. Our studies identify and focus on a TAD {\textquoteleft}fusion{\textquoteright} event associated with absence of CTCF-mediated insulation, enabling direct interactions between the MYC promoter and a distal super-enhancer. Moreover, our data also demonstrate that small-molecule inhibitors targeting either oncogenic signal transduction or epigenetic regulation can alter specific 3D interactions found in leukemia. Overall, our study highlights the impact, complexity and dynamic nature of 3D chromatin architecture in human acute leukemia.",

author = "Andreas Kloetgen and Palaniraja Thandapani and Panagiotis Ntziachristos and Yohana Ghebrechristos and Sofia Nomikou and Charalampos Lazaris and Xufeng Chen and Hai Hu and Sofia Bakogianni and Jingjing Wang and Yi Fu and Francesco Boccalatte and Hua Zhong and Elisabeth Paietta and Thomas Trimarchi and Yixing Zhu and {Van Vlierberghe}, Pieter and Inghirami, {Giorgio G.} and Timothee Lionnet and Iannis Aifantis and Aristotelis Tsirigos",

note = "Funding Information: We thank all members of the Aifantis and Tsirigos laboratories for discussions throughout this project; A. Heguy and the NYU Genome Technology Center (supported in part by National Institutes of Health (NIH)/National Cancer Institute (NCI) grant P30CA016087-30) for expertise with sequencing experiments; the NYU Flow Cytometry facility for expert cell sorting; the Applied Bioinformatics Laboratory for computational assistance; and Genewiz for expertise with sequencing experiments. This work has used computing resources at the High-Performance Computing Facility at the NYU Medical Center. We would also like to acknowledge B. Ren and A. Schmitt for their support on the Hi-C experiments. I.A. is supported by the NCI/NIH (1P01CA229086, 1R01CA228135, R01CA216421, R01CA202025, R01CA133379, R01CA149655 and 1R01CA194923), Alex{\textquoteright}s Lemonade Stand Cancer Research Foundation, the Chemotherapy Foundation, the Leukemia and Lymphoma Society and the NYSTEM program of the New York State Health Department. A.T. is supported by the American Cancer Society (RSG-15-189-01-RMC), the NCI/NIH (1P01CA229086), the Leukemia and Lymphoma Society and St. Baldrick{\textquoteright}s Foundation. P.T. was previously supported by an AACR Incyte Corporation Leukemia Research Fellowship and is currently supported by a Young Investigator Grant from Alex{\textquoteright}s Lemonade Stand Cancer Research Foundation. P.N. was supported by the NCI (R00CA188293), the American Society of Hematology, the Zell Foundation, the H Foundation and a grant (U54CA193419) from the NCI and the Chicago Region Physical Sciences–Oncology Center (CR-PSOC). P.V.V. was supported by a European Research Council Starting Grant (639784). T.L. is supported by the National Institute of General Medical Sciences (NIGMS)/NIH (R01GM127538). F.B. is supported by a Young Investigator Grant from Alex{\textquoteright}s Lemonade Stand Cancer Research Foundation. S.N. is supported by the Onassis Foundation (scholarship ID F ZP 036-1/2019-2020). Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2020",

month = apr,

day = "1",

doi = "10.1038/s41588-020-0602-9",

language = "English (US)",

volume = "52",

pages = "388--400",

journal = "Nature Genetics",

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Kloetgen, A, Thandapani, P, Ntziachristos, P, Ghebrechristos, Y, Nomikou, S, Lazaris, C, Chen, X, Hu, H, Bakogianni, S, Wang, J, Fu, Y, Boccalatte, F, Zhong, H, Paietta, E, Trimarchi, T, Zhu, Y, Van Vlierberghe, P, Inghirami, GG, Lionnet, T, Aifantis, I & Tsirigos, A 2020, 'Three-dimensional chromatin landscapes in T cell acute lymphoblastic leukemia', Nature Genetics, vol. 52, no. 4, pp. 388-400. https://doi.org/10.1038/s41588-020-0602-9

TY - JOUR

T1 - Three-dimensional chromatin landscapes in T cell acute lymphoblastic leukemia

AU - Kloetgen, Andreas

AU - Thandapani, Palaniraja

AU - Ntziachristos, Panagiotis

AU - Ghebrechristos, Yohana

AU - Nomikou, Sofia

AU - Lazaris, Charalampos

AU - Chen, Xufeng

AU - Hu, Hai

AU - Bakogianni, Sofia

AU - Wang, Jingjing

AU - Fu, Yi

AU - Boccalatte, Francesco

AU - Zhong, Hua

AU - Paietta, Elisabeth

AU - Trimarchi, Thomas

AU - Zhu, Yixing

AU - Van Vlierberghe, Pieter

AU - Inghirami, Giorgio G.

AU - Lionnet, Timothee

AU - Aifantis, Iannis

AU - Tsirigos, Aristotelis

N1 - Funding Information: We thank all members of the Aifantis and Tsirigos laboratories for discussions throughout this project; A. Heguy and the NYU Genome Technology Center (supported in part by National Institutes of Health (NIH)/National Cancer Institute (NCI) grant P30CA016087-30) for expertise with sequencing experiments; the NYU Flow Cytometry facility for expert cell sorting; the Applied Bioinformatics Laboratory for computational assistance; and Genewiz for expertise with sequencing experiments. This work has used computing resources at the High-Performance Computing Facility at the NYU Medical Center. We would also like to acknowledge B. Ren and A. Schmitt for their support on the Hi-C experiments. I.A. is supported by the NCI/NIH (1P01CA229086, 1R01CA228135, R01CA216421, R01CA202025, R01CA133379, R01CA149655 and 1R01CA194923), Alex’s Lemonade Stand Cancer Research Foundation, the Chemotherapy Foundation, the Leukemia and Lymphoma Society and the NYSTEM program of the New York State Health Department. A.T. is supported by the American Cancer Society (RSG-15-189-01-RMC), the NCI/NIH (1P01CA229086), the Leukemia and Lymphoma Society and St. Baldrick’s Foundation. P.T. was previously supported by an AACR Incyte Corporation Leukemia Research Fellowship and is currently supported by a Young Investigator Grant from Alex’s Lemonade Stand Cancer Research Foundation. P.N. was supported by the NCI (R00CA188293), the American Society of Hematology, the Zell Foundation, the H Foundation and a grant (U54CA193419) from the NCI and the Chicago Region Physical Sciences–Oncology Center (CR-PSOC). P.V.V. was supported by a European Research Council Starting Grant (639784). T.L. is supported by the National Institute of General Medical Sciences (NIGMS)/NIH (R01GM127538). F.B. is supported by a Young Investigator Grant from Alex’s Lemonade Stand Cancer Research Foundation. S.N. is supported by the Onassis Foundation (scholarship ID F ZP 036-1/2019-2020). Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2020/4/1

Y1 - 2020/4/1

N2 - Differences in three-dimensional (3D) chromatin architecture can influence the integrity of topologically associating domains (TADs) and rewire specific enhancer–promoter interactions, impacting gene expression and leading to human disease. Here we investigate the 3D chromatin architecture in T cell acute lymphoblastic leukemia (T-ALL) by using primary human leukemia specimens and examine the dynamic responses of this architecture to pharmacological agents. Systematic integration of matched in situ Hi-C, RNA-seq and CTCF ChIP–seq datasets revealed widespread differences in intra-TAD chromatin interactions and TAD boundary insulation in T-ALL. Our studies identify and focus on a TAD ‘fusion’ event associated with absence of CTCF-mediated insulation, enabling direct interactions between the MYC promoter and a distal super-enhancer. Moreover, our data also demonstrate that small-molecule inhibitors targeting either oncogenic signal transduction or epigenetic regulation can alter specific 3D interactions found in leukemia. Overall, our study highlights the impact, complexity and dynamic nature of 3D chromatin architecture in human acute leukemia.

AB - Differences in three-dimensional (3D) chromatin architecture can influence the integrity of topologically associating domains (TADs) and rewire specific enhancer–promoter interactions, impacting gene expression and leading to human disease. Here we investigate the 3D chromatin architecture in T cell acute lymphoblastic leukemia (T-ALL) by using primary human leukemia specimens and examine the dynamic responses of this architecture to pharmacological agents. Systematic integration of matched in situ Hi-C, RNA-seq and CTCF ChIP–seq datasets revealed widespread differences in intra-TAD chromatin interactions and TAD boundary insulation in T-ALL. Our studies identify and focus on a TAD ‘fusion’ event associated with absence of CTCF-mediated insulation, enabling direct interactions between the MYC promoter and a distal super-enhancer. Moreover, our data also demonstrate that small-molecule inhibitors targeting either oncogenic signal transduction or epigenetic regulation can alter specific 3D interactions found in leukemia. Overall, our study highlights the impact, complexity and dynamic nature of 3D chromatin architecture in human acute leukemia.

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EP - 400

JO - Nature Genetics

JF - Nature Genetics

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ER -

Three-dimensional chromatin landscapes in T cell acute lymphoblastic leukemia

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