The role of Nuclear phosphoinositides in epigenetic signalling

核磷酸肌醇在表观遗传信号中的作用

基本信息

批准号：
BB/N016823/1
负责人：
Nullin Divecha
金额：
$ 53.97万
依托单位：
University of Southampton
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FN016823%2F1
关键词：
role Nuclear phosphoinositides epigenetic signalling

项目摘要

If genetics is represented by a book containing the sequence of DNA encoding humans then epigenetics can be considered as the notes written in the margins by a previous reader. They do not alter the code itself but remind and instruct the next reader how they might interpret the written code. Epigenetics provides the means for environmental signals, such as how much food has been eaten or how warm it is, to be written on top of the genetic code to help instruct how cells and organisms might respond. Like the DNA code the notes can also be inherited. In essence epigenetics provides a rational model for the nature versus nurture hypothesis. DNA is complexed with proteins to form a structure called chromatin that enables the large amount of DNA to be packed into the very small volume of the cell. Problematically this packing prevents the DNA from being used easily. The epigenetic notes which are deposited on to the components of chromatin help to pack and un-pack the chromatin. The notes are deposited, removed and interpreted by a series of enzyme complexes. Exactly how these complexes are regulated in response to environmental signals is not very well understood. We have found that one of these enzyme complexes is regulated by an enzyme called PIP5K1A. In response to environmental signals PIP5K1A produces a small molecule called PIP2. Our studies suggest that PIP2 sticks to the enzyme complex and controls how well it works. This leads to changes in the epigenetic notes that are deposited and eventually to how the cell behaves. In this way we think that PIP2 acts a messenger informing and controlling the enzyme complex in response to changes in the environment. In this proposal we intend to understand how PIP2 sticks to and changes how well the enzyme complex works. The enzyme complex is made up of many different protein components and we have found that one of these proteins can stick to PIP2. By using different molecular technologies we want to find out exactly how PIP2 sticks to this protein and if this alters how well the enzyme complex deposits the epigenetic notes. Understanding the molecular details of this process is important as it increases our basic understanding of how cells respond to their environment. Furthermore the enzyme complexes that deposit epigenetic notes often do not work properly which can change how organisms age. It can also lead to the development of different human diseases such as cancer and diabetes. Understanding how the enzyme complexes are controlled will help us to design medicines that alter how well these complexes work which could be useful in modulating how well we age and how we combat diseases.

如果遗传学用一本包含编码人类的 DNA 序列的书来代表，那么表观遗传学可以被视为以前的读者在页边空白处写的笔记。他们不会改变代码本身，而是提醒和指导下一个读者如何解释编写的代码。表观遗传学提供了将环境信号（例如吃了多少食物或温度有多高）写入遗传密码的方法，以帮助指导细胞和生物体如何反应。与 DNA 密码一样，这些音符也可以遗传。本质上，表观遗传学为先天与后天假说提供了一个合理的模型。 DNA 与蛋白质复合形成一种称为染色质的结构，使大量 DNA 能够被包装到非常小的细胞体积中。问题在于，这种包装会阻碍 DNA 的轻易使用。沉积在染色质成分上的表观遗传注释有助于包装和解开染色质。这些音符由一系列酶复合物沉积、去除和解释。这些复合物是如何响应环境信号而被调节的，目前还不是很清楚。我们发现其中一种酶复合物受到一种名为 PIP5K1A 的酶的调节。为了响应环境信号，PIP5K1A 产生一种称为 PIP2 的小分子。我们的研究表明，PIP2 粘附在酶复合物上并控制其发挥作用。这会导致沉积的表观遗传记录发生变化，并最终导致细胞的行为方式发生变化。通过这种方式，我们认为 PIP2 充当了一个信使，通知和控制酶复合物以响应环境的变化。在本提案中，我们打算了解 PIP2 如何粘附并改变酶复合物的工作效果。该酶复合物由许多不同的蛋白质成分组成，我们发现其中一种蛋白质可以粘附在 PIP2 上。通过使用不同的分子技术，我们希望确切地了解 PIP2 如何粘附到这种蛋白质上，以及这是否会改变酶复合物沉积表观遗传注释的程度。了解这个过程的分子细节很重要，因为它增加了我们对细胞如何对其环境做出反应的基本了解。此外，沉积表观遗传信息的酶复合物通常无法正常工作，这可能会改变生物体的衰老方式。它还可能导致癌症和糖尿病等不同人类疾病的发生。了解酶复合物的控制方式将有助于我们设计能够改变这些复合物发挥作用的药物，从而有助于调节我们的衰老程度和对抗疾病的方式。