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Whole-genome doubling drives oncogenic loss of chromatin segregation.
Lambuta, Ruxandra A; Nanni, Luca; Liu, Yuanlong; Diaz-Miyar, Juan; Iyer, Arvind; Tavernari, Daniele; Katanayeva, Natalya; Ciriello, Giovanni; Oricchio, Elisa.
Afiliação
  • Lambuta RA; Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, EPFL, Écublens, Switzerland.
  • Nanni L; Swiss Cancer Center Leman, Lausanne, Switzerland.
  • Liu Y; Swiss Cancer Center Leman, Lausanne, Switzerland.
  • Diaz-Miyar J; Department of Computational Biology, University of Lausanne (UNIL), Lausanne, Switzerland.
  • Iyer A; Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
  • Tavernari D; Swiss Cancer Center Leman, Lausanne, Switzerland.
  • Katanayeva N; Department of Computational Biology, University of Lausanne (UNIL), Lausanne, Switzerland.
  • Ciriello G; Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
  • Oricchio E; Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, EPFL, Écublens, Switzerland.
Nature ; 615(7954): 925-933, 2023 03.
Article em En | MEDLINE | ID: mdl-36922594
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cromatina / Genoma Humano / Aberrações Cromossômicas / Cromossomos Humanos / Segregação de Cromossomos / Neoplasias Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cromatina / Genoma Humano / Aberrações Cromossômicas / Cromossomos Humanos / Segregação de Cromossomos / Neoplasias Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article