High-fidelity epigenetic maintenance in somatic cells: CIZ1 assemblies as molecular shield

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，它们逐渐关闭不需要的基因，直到它们只产生对其功能至关重要的产物。限制他们选择的方法之一是通过化学修饰与要关闭的基因密切相关的特定蛋白质（组蛋白）。一旦建立，这些修饰必须是稳定的，并且在每次细胞分裂时也进行复制，以便子细胞具有与其父母相同的库，因此可以获得与其父母相同的基因。我们正在研究确保组蛋白修饰忠实维持的过程;阻止细胞偏离其路径的“质量控制”。修饰由酶添加并由其他酶去除，因此这些之间的平衡以及它们获得组蛋白的相对能力决定了特定细胞中是否存在特定的组蛋白修饰。这是细胞“是什么”的基础，因为它控制着它可以表达哪些基因。最近，我们发现一种名为CIZ 1的蛋白质影响至少三种不同组蛋白修饰的稳定性，因此当CIZ 1不能在细胞核内形成大的组装体时，它们就不存在了。我们认为，这些组装体通常会在选定的基因及其组蛋白周围形成一个屏障，以保护它们免受酶的破坏。该项目旨在了解对屏蔽完整性的干扰是否会破坏细胞的稳定性，使它们走上一条可能导致疾病甚至衰老的道路。我们特别想探索已经与人类疾病相关的CIZ 1片段是否可以通过CIZ 1组件的不稳定来启动细胞变性。我们的目标是利用这些信息来考虑我们如何干预（药物或饮食）以防止CIZ 1组装不稳定。我们还想知道在正常发育过程中是否会发生对盾牌组装的干扰，以改变“开启”和“关闭”酶之间的平衡。在可能的干预行动中理解这一点很重要。最后，我们计划测试有多少不同的组蛋白修饰依赖于CIZ 1，以及在什么条件下。到目前为止，我们的分析一直是在从仍在发育的小鼠胚胎中提取的细胞中进行的，因此重要的是要将图片扩大到从成年小鼠和最终人类中提取的分裂和非分裂细胞。

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 chemical modification of specific proteins (histones) that are closely associated with the genes to be shut down. Once established, these modifications must be stable, and also copied each time a cell divides so that daughter cells have the same repertoire as their parents, and therefore access the same genes as their parents. We are studying the processes that ensure histone modifications are faithfully maintained; the 'quality control' that stops a cell from drifting away from its path. Modifications are added by enzymes and removed by other enzymes, so the balance between these, and their relative ability to gain access to histones, governs whether specific histone modifications exist in a particular cell. This is fundamental to what the cell 'is' because it controls which genes it can express. Recently we showed that a protein called CIZ1 influences the stability of at least three different histone modifications, so that they are absent when CIZ1 is not able to form large assemblies inside the nucleus of cells. We think that these assemblies normally form a shield around selected genes and their histones, to protect them from the enzymes that remove the modifications. This project aims to understand whether interference with shield integrity can destabilize cells, setting them off down a path that could contribute to disease, and possibly aging. We specifically want to explore whether fragments of CIZ1 that are already associated with human diseases, can initiate cellular degeneration by destabilization of CIZ1 assemblies. We aim to use the information to consider how we might intervene (with drugs or diet) to prevent CIZ1 assembly destabilization.We also want to know whether interference with shield assembly ever happens during normal development, as a way of shifting the balance between 'on' and 'off' enzymes. This would be important to understand in the context of possible interventions. Finally, we plan to test how many different histone modifications are dependent on CIZ1, and under what conditions. So far, our analysis has been in cells taken from mouse embryos that are still developing, so it will be important to widen the picture to dividing and non-dividing cells taken from adult mice, and eventually humans.