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对特定蛋白质(组蛋白)进行化学修饰，这些蛋白质与要关闭的基因密切相关。一旦确定，这些修饰必须是稳定的，并在每次细胞分裂时复制，以便子代细胞拥有与父母相同的谱系，从而获得与父母相同的基因。我们正在研究确保组蛋白修饰得到忠实维持的过程，即阻止细胞偏离其路径的“质量控制”。修饰是由酶添加的，并被其他酶移除，所以这些修饰之间的平衡，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CIZ1的蛋白质会影响至少三种不同的组蛋白修饰的稳定性，因此当CIZ1不能在细胞核内形成大的组装时，它们就不存在。我们认为，这些组装通常会在选定的基因及其组蛋白周围形成一层屏障，以保护它们免受移除修饰的酶的影响。该项目旨在了解干扰屏蔽完整性是否会破坏细胞的稳定，使它们走上一条可能导致疾病，甚至可能衰老的道路。我们特别想探索已经与人类疾病相关的CIZ1片段是否会通过CIZ1组装的不稳定而引发细胞退化。我们的目标是利用这些信息来考虑我们可能如何干预(通过药物或饮食)来防止CIZ1组装的不稳定。我们还想知道在正常发育过程中是否会发生对屏蔽组装的干扰，作为一种改变‘开’和‘关’酶之间的平衡的方式。在可能的干预背景下理解这一点将是重要的。最后，我们计划测试有多少不同的组蛋白修饰依赖于CIZ1，以及在什么条件下。到目前为止，我们的分析是从仍在发育中的小鼠胚胎中提取的细胞，因此将研究范围扩大到成年小鼠以及最终人类的分裂和非分裂细胞将是很重要的。

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.