Turvey Gabrielle L, López de Alba Ernesto, Stewart Emma, Cook Heather, Alalti Ahmad, Gawne Richard T, Ainscough Justin F-X, Mason Andrew S, Coverley Dawn
Mammalian Cell Cycle Research Group, Department of Biology, University of York, York, UK.
York Biomedical Research Institute, University of York , York, UK.
J Cell Biol. 2025 May 5;224(5). doi: 10.1083/jcb.202409123. Epub 2025 Mar 11.
CIZ1 is part of the RNA-dependent supramolecular assemblies that form around the inactive X-chromosome (Xi) in female cells and smaller assemblies throughout the nucleus in both sexes. Here, we show that CIZ1 C-terminal anchor domain (AD) is elevated in human breast tumor transcriptomes, even at stage I. Elevation correlates with deprotection of chromatin and upregulation of lncRNA-containing gene clusters in ∼10 Mb regions enriched in cancer-associated genes. We modeled the effect of AD on endogenous CIZ1-Xi assemblies and observed dominant-negative interference with their reformation after mitosis, leading to abnormal assemblies similar to those in breast cancer cells, and depletion of H2AK119ub1, H3K27me3, and Xist. Consistent alterations in gene expression were evident across the genome, showing that AD-mediated interference has a destabilizing effect, likely by unscheduled exposure of underlying chromatin to modifying enzymes. The data argue for a dominant, potent, and rapid effect of CIZ1 AD that can deprogram gene expression patterns and which may predispose incipient tumors to epigenetic instability.
CIZ1是RNA依赖性超分子组装体的一部分，该组装体在雌性细胞的失活X染色体（Xi）周围形成，在两性的整个细胞核中也形成较小的组装体。在这里，我们表明CIZ1 C端锚定结构域（AD）在人类乳腺肿瘤转录组中升高，即使在I期也是如此。这种升高与染色质去保护以及在富含癌症相关基因的约10 Mb区域中含lncRNA基因簇的上调相关。我们模拟了AD对内源性CIZ1-Xi组装体的影响，并观察到其对有丝分裂后组装体重塑的显性负性干扰，导致类似于乳腺癌细胞中的异常组装体，并使H2AK119ub1、H3K27me3和Xist耗竭。全基因组范围内基因表达出现一致变化，表明AD介导的干扰具有破坏稳定性的作用，可能是由于潜在染色质意外暴露于修饰酶所致。这些数据表明CIZ1 AD具有显著、强大且快速的作用，能够使基因表达模式去程序化，并可能使早期肿瘤易发生表观遗传不稳定。
