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Pervasive structural heterogeneity rewires glioblastoma chromosomes to sustain patient-specific transcriptional programs

Author

Listed:
  • Ting Xie

    (University Medical Center Göttingen)

  • Adi Danieli-Mackay

    (University Medical Center Göttingen)

  • Mariachiara Buccarelli

    (Istituto Superiore di Sanità)

  • Mariano Barbieri

    (University Medical Center Göttingen)

  • Ioanna Papadionysiou

    (University Medical Center Göttingen)

  • Q. Giorgio D’Alessandris

    (Catholic University School of Medicine
    Fondazione Policlinico Universitario A. Gemelli IRCCS)

  • Claudia Robens

    (University of Cologne)

  • Nadine Übelmesser

    (University Medical Center Göttingen)

  • Omkar Suhas Vinchure

    (University Hospital and Heinrich-Heine-University Düsseldorf)

  • Liverana Lauretti

    (Catholic University School of Medicine)

  • Giorgio Fotia

    (Research and Development in Sardinia (CRS4))

  • Roland F. Schwarz

    (University of Cologne
    Berlin Institute for the Foundations of Learning and Data (BIFOLD))

  • Xiaotao Wang

    (Fudan University
    Chinese Academy of Medical Sciences)

  • Lucia Ricci-Vitiani

    (Istituto Superiore di Sanità)

  • Jay Gopalakrishnan

    (University Hospital and Heinrich-Heine-University Düsseldorf
    Jena University Hospital and Friedrich Schiller University of Jena)

  • Roberto Pallini

    (Catholic University School of Medicine)

  • Argyris Papantonis

    (University Medical Center Göttingen)

Abstract

Glioblastoma multiforme (GBM) encompasses brain malignancies marked by phenotypic and transcriptional heterogeneity thought to render these tumors aggressive, resistant to therapy, and inevitably recurrent. However, little is known about how the spatial organization of GBM genomes underlies this heterogeneity and its effects. Here, we compile a cohort of 28 patient-derived glioblastoma stem cell-like lines (GSCs) known to reflect the properties of their tumor-of-origin; six of these were primary-relapse tumor pairs from the same patient. We generate and analyze 5 kbp-resolution chromosome conformation capture (Hi-C) data from all GSCs to systematically map thousands of standalone and complex structural variants (SVs) and the multitude of neoloops arising as a result. By combining Hi-C, histone modification, and gene expression data with chromatin folding simulations, we explain how the pervasive, uneven, and idiosyncratic occurrence of neoloops sustains tumor-specific transcriptional programs via the formation of new enhancer-promoter contacts. We also show how even moderately recurrent neoloops can relate to patient-specific vulnerabilities. Together, our data provide a resource for dissecting GBM biology and heterogeneity, as well as for informing therapeutic approaches.

Suggested Citation

  • Ting Xie & Adi Danieli-Mackay & Mariachiara Buccarelli & Mariano Barbieri & Ioanna Papadionysiou & Q. Giorgio D’Alessandris & Claudia Robens & Nadine Übelmesser & Omkar Suhas Vinchure & Liverana Laure, 2024. "Pervasive structural heterogeneity rewires glioblastoma chromosomes to sustain patient-specific transcriptional programs," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48053-2
    DOI: 10.1038/s41467-024-48053-2
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    References listed on IDEAS

    as
    1. Lucia Ricci-Vitiani & Roberto Pallini & Mauro Biffoni & Matilde Todaro & Gloria Invernici & Tonia Cenci & Giulio Maira & Eugenio Agostino Parati & Giorgio Stassi & Luigi Maria Larocca & Ruggero De Mar, 2010. "Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells," Nature, Nature, vol. 468(7325), pages 824-828, December.
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