Epigenetic instability caused by absence of CIZ1 drives transformation during quiescence cycles.
Epigenetic instability caused by absence of CIZ1 drives transformation during quiescence cycles.
复制标题
DOI：
10.1186/s12915-023-01671-6
复制
发表时间：
2023-08-15
期刊：
影响因子：
5.4
通讯作者：
Coverley, Dawn
中科院分区：
文献类型：
--
作者：
Dobbs, Olivia G.;Wilson, Rosemary H. C.;Newling, Katherine;Ainscough, Justin F. -X.;Coverley, Dawn
Cip 1相互作用的锌指蛋白1（CIZ 1）形成RNA依赖的蛋白质组装体，稳定表观遗传状态，在女性的失活X染色体上值得注意。CIZ 1与一系列人类癌症有关，在小鼠中，CIZ 1的遗传缺失表现为雌性的过度增殖淋巴谱系。这表明它在维持表观遗传稳定性方面的作用与疾病有关。在这里，我们表明，男性和女性CIZ 1空原代鼠成纤维细胞减少H4 K20 me 1，这妥协进入静止核凝聚。全球转录抑制在缩合缺陷CIZ 1无效细胞中保持完整;然而，与染色质缩合和同源定向DNA修复相关的基因子集受到干扰。在WT细胞中，通过操作H4 K20 me 1甲基转移酶SET 8在表型上模拟未能缩合，并在CIZ 1再表达后在CIZ 1缺失细胞中部分逆转。至关重要的是，在从静止期退出期间，核去凝聚保持活跃，使得重复的进入和退出循环引起对机械应力敏感的膨胀的核、DNA损伤检查点激活和转化的增殖集落的下游出现。我们的研究结果表明CIZ 1在进入静止期时染色质凝聚中的作用，并探讨了CIZ 1无效细胞中这种缺陷的后果。总之，这些数据表明CIZ 1对表观基因组的保护可以防止基因组在静止周期中的不稳定性。这将CIZ 1的丢失确定为经历静止进入和退出周期的细胞中的潜在破坏性脆弱性。在线版本包含补充材料，可通过10.1186/s12915-023-01671-6获得。
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. The online version contains supplementary material available at 10.1186/s12915-023-01671-6.
登录
查看更多内容
影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
14.9
作者：
Fischer M;Grossmann P;Padi M;DeCaprio JA
通讯作者：
DeCaprio JA
影响因子：
9.8
作者：
Coller HA;Sang L;Roberts JM
通讯作者：
Roberts JM
影响因子：
4.8
作者：
Houston, Sabrina I.;McManus, Kirk J.;Rice, Judd C.
通讯作者：
Rice, Judd C.
DOI：
10.1038/nrm3591
发表时间：
2013-06
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--