Role of CIZ1 in maintenance of epigenetic landscape in primary differentiated cells

CIZ1 在维持初级分化细胞表观遗传景观中的作用

• 批准号: MR/R008981/1
• 负责人: Dawn Coverley
• 金额: $ 51.97万
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR008981%2F1
• 关键词: Role; CIZ1; maintenance; epigenetic; landscape

Cells in a developing embryo have the capability to become all of the different types of cell in the adult body. As they specialize they gradually turn off genes that are not required, until they only produce products that are essential to their function. One of the ways that their choice is restricted is by modification of specific proteins that are closely associated with the genes to be shut down. Once established, these modifications, or marks, must be copied each time a cell divides so that daughter cells have the same marks as their parents, and therefore access the same repertoire of genes as their parents. We are studying the mechanism that ensures marks are faithfully copied; the 'quality control' process that stops a cell from drifting away from its chosen path.Specifically, we are interested in how the chosen genes and the proteins that add the marks (factors) find each other among the mass of DNA packed into the cell nucleus. Do the factors diffuse around the nucleus until they happen to come across the correct genes, or is there a delivery system that ensures 'letters' reach the right 'address' in good time? Our experiments will look at whether, in normal cells, the factors are confined to factory sites, restricting their ability to diffuse around. This would mean that genes must visit factories to be marked, which could afford tight control over the process. So far, there has been very little investigation of this because (our data suggest) restriction to factories appears to be absent or overridden in most of the cell types that are commonly used by researchers (stem cells, cancer cells, cultured cells). In order to understand whether restriction to factories is the norm for non-diseased cells in the body, it is necessary to work with newly isolated cells that have not been adapted to long-term growth in a laboratory. Typically, adapted cells have undergone changes that are similar to changes that take place in cancer cells, and appear to have lost the ability to restrict key factors to factories. Only by studying newly isolated cells will we understand how normal cells maintain their choice of genes, and then be able to understand how this is eroded during the early stages of cancer.Recently we showed that a protein called CIZ1 is required, in normal cells, for a test chromosome to i) acquire key marks and ii) briefly relocate from one position in the nucleus to another position. We think that these two observations are linked and that, by studying the function of CIZ1 we can establish whether targeted delivery of gene to spatially restricted factor normally operates inside the nucleus of normal cells in the body. We aim to use the results to understand how important CIZ1 is to maintain appropriate marks, and so guard against loss of control and emergence of disease. We are specifically concerned with the effect of alterations in CIZ1 (common in early stage cancers of several different types), as experimental removal of CIZ1 promotes the apparent tendency of cultured cells to loosen spatial separation of gene and factor.

发育中的胚胎中的细胞有能力成为成人体内所有不同类型的细胞。随着它们的专门化，它们逐渐关闭了不需要的基因，直到它们只产生对其功能至关重要的产品。他们的选择受到限制的方式之一是通过修改与要关闭的基因密切相关的特定蛋白质。一旦确定，这些修改或标记必须在每次细胞分裂时复制，以便子代细胞拥有与父母细胞相同的标记，从而获得与父母细胞相同的基因库。我们正在研究确保标记被忠实复制的机制；即阻止细胞偏离其选定路径的“质量控制”过程。具体地说，我们感兴趣的是，选定的基因和添加标记(因子)的蛋白质如何在装入细胞核的大量DNA中找到彼此。这些因子是否在细胞核内扩散，直到它们碰巧遇到正确的基因，或者是否存在一种传递系统，以确保“信件”及时到达正确的“地址”？我们的实验将考察在正常细胞中，这些因素是否仅限于工厂场所，从而限制它们扩散的能力。这将意味着基因必须访问工厂才能被标记，这可能会对这一过程进行严格控制。到目前为止，对此的研究很少，因为(我们的数据表明)在研究人员常用的大多数细胞类型(干细胞、癌细胞、培养细胞)中，似乎没有或忽略了对工厂的限制。为了了解对工厂的限制是否是体内未患病细胞的标准，有必要处理新分离的细胞，这些细胞尚未适应实验室的长期生长。通常情况下，适应的细胞经历了类似于癌细胞发生的变化，似乎已经失去了将关键因素限制在工厂的能力。只有通过研究新分离的细胞，我们才能理解正常细胞如何保持他们对基因的选择，然后才能理解这种选择在癌症早期是如何被侵蚀的。最近我们证明，在正常细胞中，测试染色体需要一种名为CIZ1的蛋白质来i)获得关键标记和ii)从细胞核中的一个位置短暂地重新定位到另一个位置。我们认为这两个观察结果是有联系的，通过研究CIZ1的功能，我们可以确定靶向运送基因到空间受限因子是否在人体正常细胞的细胞核内正常运作。我们的目标是利用这些结果来理解CIZ1保持适当分数的重要性，从而防止失去控制和疾病的出现。我们特别关注CIZ1(在几种不同类型的早期癌症中常见)的变化的影响，因为实验中移除CIZ1促进了培养细胞放松基因和因子空间分离的明显趋势。

项目成果

Prion-like domains drive CIZ1 assembly formation at the inactive X chromosome.

• DOI: 10.1083/jcb.202103185
• 发表时间: 2022-04-04
• 期刊: The Journal of cell biology
• 作者: Sofi S;Williamson L;Turvey GL;Scoynes C;Hirst C;Godwin J;Brockdorff N;Ainscough J;Coverley D
• 通讯作者: Coverley D

Dominant CIZ1 fragments drive epigenetic instability and are expressed in early stage cancers

• DOI: 10.1101/2023.09.22.558821
• 发表时间: 2023-09
• 期刊: bioRxiv
• 作者: Gabrielle L. Turvey;Ernesto López de Alba;Emma R Stewart;Lewis Byrom;Heather Cook;Sajad Sofi;Ahmad Alalti;J. Ainscough;Andrew Mason;A. Antson;D. Coverley

CIZ1 in Xist seeded assemblies at the inactive X chromosome.

• DOI: 10.3389/fcell.2023.1296600
• 发表时间: 2023
• 期刊: FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
• 影响因子: 5.5
• 作者: Sofi, Sajad;Coverley, Dawn
• 通讯作者: Coverley, Dawn

A polyglutamine domain is required for de novo CIZ1 assembly formation at the inactive X chromosome

在失活的 X 染色体上从头形成 CIZ1 组装需要多聚谷氨酰胺结构域

• DOI: 10.1101/2020.11.10.376558
• 发表时间: 2020
• 作者: Sofi S