Whole-genome doubling drives oncogenic loss of chromatin segregation

Ruxandra A. Lambuta, Luca Nanni, Yuanlong Liu, Juan Diaz-Miyar, Arvind Iyer, Daniele Tavernari, Natalya Katanayeva, Giovanni Ciriello () and Elisa Oricchio ()
Additional contact information
Ruxandra A. Lambuta: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, EPFL
Luca Nanni: Swiss Cancer Center Leman
Yuanlong Liu: Swiss Cancer Center Leman
Juan Diaz-Miyar: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, EPFL
Arvind Iyer: Swiss Cancer Center Leman
Daniele Tavernari: Swiss Cancer Center Leman
Natalya Katanayeva: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, EPFL
Giovanni Ciriello: Swiss Cancer Center Leman
Elisa Oricchio: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, EPFL

Nature, 2023, vol. 615, issue 7954, 925-933

Abstract: 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.

Date: 2023
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41586-023-05794-2 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:615:y:2023:i:7954:d:10.1038_s41586-023-05794-2

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-023-05794-2

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().