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Whole-genome doubling drives oncogenic loss of chromatin segregation

Author

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  • Ruxandra A. Lambuta

    (Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, EPFL
    Swiss Cancer Center Leman)

  • Luca Nanni

    (Swiss Cancer Center Leman
    University of Lausanne (UNIL)
    Swiss Institute of Bioinformatics (SIB))

  • Yuanlong Liu

    (Swiss Cancer Center Leman
    University of Lausanne (UNIL)
    Swiss Institute of Bioinformatics (SIB))

  • Juan Diaz-Miyar

    (Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, EPFL
    Swiss Cancer Center Leman)

  • Arvind Iyer

    (Swiss Cancer Center Leman
    University of Lausanne (UNIL)
    Swiss Institute of Bioinformatics (SIB))

  • Daniele Tavernari

    (Swiss Cancer Center Leman
    University of Lausanne (UNIL)
    Swiss Institute of Bioinformatics (SIB))

  • Natalya Katanayeva

    (Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, EPFL
    Swiss Cancer Center Leman)

  • Giovanni Ciriello

    (Swiss Cancer Center Leman
    University of Lausanne (UNIL)
    Swiss Institute of Bioinformatics (SIB))

  • Elisa Oricchio

    (Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, EPFL
    Swiss Cancer Center Leman)

Abstract

Whole-genome doubling (WGD) is a recurrent event in human cancers and it promotes chromosomal instability and acquisition of aneuploidies1–8. However, the three-dimensional organization of chromatin in WGD cells and its contribution to oncogenic phenotypes are currently unknown. Here we show that in p53-deficient cells, WGD induces loss of chromatin segregation (LCS). This event is characterized by reduced segregation between short and long chromosomes, A and B subcompartments and adjacent chromatin domains. LCS is driven by the downregulation of CTCF and H3K9me3 in cells that bypassed activation of the tetraploid checkpoint. Longitudinal analyses revealed that LCS primes genomic regions for subcompartment repositioning in WGD cells. This results in chromatin and epigenetic changes associated with oncogene activation in tumours ensuing from WGD cells. Notably, subcompartment repositioning events were largely independent of chromosomal alterations, which indicates that these were complementary mechanisms contributing to tumour development and progression. Overall, LCS initiates chromatin conformation changes that ultimately result in oncogenic epigenetic and transcriptional modifications, which suggests that chromatin evolution is a hallmark of WGD-driven cancer.

Suggested Citation

  • Ruxandra A. Lambuta & Luca Nanni & Yuanlong Liu & Juan Diaz-Miyar & Arvind Iyer & Daniele Tavernari & Natalya Katanayeva & Giovanni Ciriello & Elisa Oricchio, 2023. "Whole-genome doubling drives oncogenic loss of chromatin segregation," Nature, Nature, vol. 615(7954), pages 925-933, March.
  • Handle: RePEc:nat:nature:v:615:y:2023:i:7954:d:10.1038_s41586-023-05794-2
    DOI: 10.1038/s41586-023-05794-2
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    Cited by:

    1. Adam C. Weiner & Marc J. Williams & Hongyu Shi & Ignacio Vázquez-García & Sohrab Salehi & Nicole Rusk & Samuel Aparicio & Sohrab P. Shah & Andrew McPherson, 2024. "Inferring replication timing and proliferation dynamics from single-cell DNA sequencing data," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Leanne M. Brown & Ryan A. Hagenson & Tilen Koklič & Iztok Urbančič & Lu Qiao & Janez Strancar & Jason M. Sheltzer, 2024. "An elevated rate of whole-genome duplications in cancers from Black patients," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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