小柯机器人

瑞士实验癌症中心Elisa Oricchio等研究人员合作发现，全基因组加倍驱动致癌性染色质分离的丧失。相关论文于2023年3月15日在线发表在《自然》杂志上。

研究人员表明，在p53缺陷的细胞中，全基因组加倍（WGD）会诱发染色质分离的丧失（LCS）。这一事件的特点是短染色体和长染色体、A和B亚区以及相邻染色质域之间的分离减少。LCS是由绕过四倍体检查点激活的细胞中CTCF和H3K9me3的下调驱动。纵向分析显示，LCS为WGD细胞中的亚区室重新定位的基因组区域提供了动力。这导致了染色质和表观遗传学的变化，与WGD细胞产生的肿瘤中的癌基因激活有关。值得注意的是，亚区室重新定位事件在很大程度上是独立于染色体改变的，这表明这些是有助于肿瘤发展和进展的互补性机制。总的来说，LCS启动了染色质构象的变化，最终导致致癌的表观遗传和转录修饰，这表明染色质演化是WGD驱动型癌症的一个标志。

据悉，WGD是人类癌症中反复出现的事件，它促进了染色体不稳定和非整倍体的获得。然而，WGD细胞中染色质的三维组织以及它对致癌表型的贡献目前还不清楚。

附：英文原文

Title: Whole-genome doubling drives oncogenic loss of chromatin segregation

Author: Lambuta, Ruxandra A., Nanni, Luca, Liu, Yuanlong, Diaz-Miyar, Juan, Iyer, Arvind, Tavernari, Daniele, Katanayeva, Natalya, Ciriello, Giovanni, Oricchio, Elisa

Issue&Volume: 2023-03-15

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 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.

DOI: 10.1038/s41586-023-05794-2

Source: https://www.nature.com/articles/s41586-023-05794-2

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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