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Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation

Roser Vilarrasa-Blasi, Paula Soler-Vila, Núria Verdaguer-Dot, Núria Russiñol, Marco Di Stefano, Vicente Chapaprieta, Guillem Clot, Irene Farabella, Pol Cuscó, Xabier Agirre, Felipe Prosper, Renée Beekman, Silvia Beà, Dolors Colomer, Henk Stunnenberg, View ORCID ProfileIvo Gut, Elias Campo, Marc A. Marti-Renom, José Ignacio Martin-Subero
doi: https://doi.org/10.1101/764910
Roser Vilarrasa-Blasi
1Institut d’lnvestigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
2Departament de Fonaments Clínics, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain
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Paula Soler-Vila
3CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
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Núria Verdaguer-Dot
1Institut d’lnvestigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
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Núria Russiñol
1Institut d’lnvestigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
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Marco Di Stefano
3CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
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Vicente Chapaprieta
1Institut d’lnvestigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
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Guillem Clot
1Institut d’lnvestigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
5Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
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Irene Farabella
3CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
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Pol Cuscó
4Gastrointestinal and Endocrine Tumors Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
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Xabier Agirre
5Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
6Área de Oncología, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Universidad de Navarra, Pamplona, Spain
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Felipe Prosper
5Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
6Área de Oncología, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Universidad de Navarra, Pamplona, Spain
7Departamento de Hematología, Clínica Universidad de Navarra, Universidad de Navarra, Pamplona, Spain
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Renée Beekman
1Institut d’lnvestigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
5Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
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Silvia Beà
1Institut d’lnvestigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
5Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
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Dolors Colomer
1Institut d’lnvestigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
5Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
8Hematopathology Section, Hospital Clinic of Barcelona, Barcelona, Spain
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Henk Stunnenberg
9Molecular Biology, NCMLS, FNWI, Radboud University, Nijmegen, The Netherlands
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Ivo Gut
3CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
10Universitat Pompeu Fabra (UPF), Barcelona, Spain
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  • ORCID record for Ivo Gut
Elias Campo
1Institut d’lnvestigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
2Departament de Fonaments Clínics, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain
5Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
11Fundació Clínic per a la Recerca Biomèdica, Barcelona, Spain
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Marc A. Marti-Renom
3CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
10Universitat Pompeu Fabra (UPF), Barcelona, Spain
12ICREA, Barcelona, Spain
13Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
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José Ignacio Martin-Subero
1Institut d’lnvestigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
2Departament de Fonaments Clínics, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain
5Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
12ICREA, Barcelona, Spain
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  • For correspondence: imartins@clinic.cat martirenom@cnag.crg.eu
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Abstract

Despite recent advances, the dynamics of genome architecture and chromatin function during human cell differentiation and its potential reorganization upon neoplastic transformation remains poorly characterized. Here, we integrate in situ Hi-C and nine additional omic layers to define and biologically characterize the dynamic changes in three-dimensional (3D) genome architecture across normal B cell differentiation and in neoplastic cells from different subtypes of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) patients. Beyond conventional active (A) and inactive (B) compartments, an integrative analysis of Hi-C data reveals the presence of a highly-dynamic intermediate compartment enriched in poised and polycomb-repressed chromatin. During B cell development, we detect that 28% of the compartments change at defined maturation stages and mostly involve the intermediate compartment. The transition from naive to germinal center B cells is associated with widespread chromatin activation, which mostly reverts into the naive state upon further maturation of germinal center cells into memory B cells. The analysis of CLL and MCL neoplastic cells points both to entity and subtype-specific alterations in chromosome organization. Remarkably, we observe that large chromatin blocks containing key disease-specific genes alter their 3D genome organization. These include the inactivation of a 2Mb region containing the EBF1 gene in CLL and the activation of a 6.1Mb region containing the SOX11 gene in clinically aggressive MCL. This study indicates that 3D genome interactions are extensively modulated during normal B cell differentiation and that the genome of B cell neoplasias acquires a tumor-specific 3D genome architecture.

Footnotes

  • ↵15 These authors have jointly supervised this work

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Posted September 12, 2019.
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Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation
Roser Vilarrasa-Blasi, Paula Soler-Vila, Núria Verdaguer-Dot, Núria Russiñol, Marco Di Stefano, Vicente Chapaprieta, Guillem Clot, Irene Farabella, Pol Cuscó, Xabier Agirre, Felipe Prosper, Renée Beekman, Silvia Beà, Dolors Colomer, Henk Stunnenberg, Ivo Gut, Elias Campo, Marc A. Marti-Renom, José Ignacio Martin-Subero
bioRxiv 764910; doi: https://doi.org/10.1101/764910
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Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation
Roser Vilarrasa-Blasi, Paula Soler-Vila, Núria Verdaguer-Dot, Núria Russiñol, Marco Di Stefano, Vicente Chapaprieta, Guillem Clot, Irene Farabella, Pol Cuscó, Xabier Agirre, Felipe Prosper, Renée Beekman, Silvia Beà, Dolors Colomer, Henk Stunnenberg, Ivo Gut, Elias Campo, Marc A. Marti-Renom, José Ignacio Martin-Subero
bioRxiv 764910; doi: https://doi.org/10.1101/764910

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