Cip1相互作用锌指蛋白1（CIZ1）形成依赖RNA的蛋白质组装体，稳定表观遗传状态，特别是在雌性体内的不活跃X染色体上。CIZ1与一系列人类癌症有关，并且在小鼠中CIZ1的遗传缺失在雌性淋巴细胞系上表现出高增殖。这表明其在表观遗传稳定性维持中的作用与疾病有关。在这里，我们展示了雄性和雌性CIZ1敲除原代小鼠成纤维细胞的H4K20me1减少，并且这会影响进入静止状态的核浓缩。全局转录抑制在浓缩缺陷的CIZ1敲除细胞中保持完整；然而，与染色质浓缩和同源定向DNA修复有关的一些基因被扰乱。未能浓缩的表型被在WT细胞中操纵H4K20me1甲基转移酶SET8而部分恢复在CIZ1敲除细胞中重新表达CIZ1。关键是，在退出静止状态过程中，核脱浓仍然活跃，因此重复进入和退出周期会产生易受机械应力、DNA损伤检查点激活和下游转化增殖结节的扩展细胞核。我们的结果证明了CIZ1在进入静止状态时对染色质浓缩的作用，并探讨了CIZ1敲除细胞中这一缺陷的后果。这些数据表明，CIZ1对表观基因组的保护在静止周期中抵御基因组不稳定。这揭示了在经历进入和退出静止循环的细胞中，CIZ1的丧失是一种潜在的毁灭性弱点。© 2023年。BioMed Central有限公司，斯普林格自然出版集团的一部分。

Cip1-interacting zinc finger protein 1 (CIZ1) forms RNA-dependent protein assemblies that stabilise epigenetic state, notable at the inactive X chromosome in females. CIZ1 has been linked with a range of human cancers and in mice genetic deletion of CIZ1 manifests as hyperproliferative lymphoid lineages in females. This suggests that its role in maintenance of epigenetic stability is linked with disease.Here, we show that male and female CIZ1-null primary murine fibroblasts have reduced H4K20me1 and that this compromises nuclear condensation on entry to quiescence. Global transcriptional repression remains intact in condensation-deficient CIZ1-null cells; however, a subset of genes linked with chromatin condensation and homology-directed DNA repair are perturbed. Failure to condense is phenotypically mimicked by manipulation of the H4K20me1 methyltransferase, SET8, in WT cells and partially reverted in CIZ1-null cells upon re-expression of CIZ1. Crucially, during exit from quiescence, nuclear decondensation remains active, so that repeated entry and exit cycles give rise to expanded nuclei susceptible to mechanical stress, DNA damage checkpoint activation, and downstream emergence of transformed proliferative colonies.Our results demonstrate a role for CIZ1 in chromatin condensation on entry to quiescence and explore the consequences of this defect in CIZ1-null cells. Together, the data show that CIZ1's protection of the epigenome guards against genome instability during quiescence cycles. This identifies loss of CIZ1 as a potentially devastating vulnerability in cells that undergo cycles of quiescence entry and exit.© 2023. BioMed Central Ltd., part of Springer Nature.