Nome rivista: Nature
Numero: 7954
Data pubblicazione: 15/03/2023

Autori:

Nome: Ruxandra
Cognome: Lambuta
Affiliazione: EPFL

Nome: Luca
Cognome: Nanni
Affiliazione: University of Lausanne

Nome: Yuanlong
Cognome: Liu
Affiliazione: University of Lausanne

Nome: Juan
Cognome: Diaz-Miyar
Affiliazione: EPFL

Nome: Arvind
Cognome: Iyer
Affiliazione: University of Lausanne

Nome: Daniele
Cognome: Tavernari
Aff iliazione: University of Lausanne

Nome: Natalya
Cognome: Katanayeva
Affiliazione: EPFL

Nome: Giovanni
Cognome: Ciriello
Affiliazione: University of Lausanne

Nome: Elisa
Cognome: Oricchio
Affiliazione: EPFL

Abstract: Whole-genome doubling (WGD) is a recurrent event in human cancers and it promotes chromosomal instability and acquisition of aneuploidies1,2,3,4,5,6,7,8. 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 epig enetic 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.
Indirizzo: https://www.nature.com/articles/s41586-023-05794-2