The role of Nuclear phosphoinositides in epigenetic signalling

核磷酸肌醇在表观遗传信号中的作用

• 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

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.

如果遗传学是一本包含人类DNA序列的书，那么表观遗传学可以被认为是以前的读者在页边空白处写的笔记。他们不改变代码本身，但提醒和指导下一个读者他们可能如何解释书面代码。表观遗传学为环境信号提供了一种手段，比如吃了多少食物或有多热，这些环境信号被写在遗传密码的上面，以帮助指导细胞和生物体如何做出反应。就像DNA密码一样，音符也可以遗传。从本质上讲，表观遗传学为先天vs后天假说提供了一个合理的模型。DNA与蛋白质结合形成一种叫做染色质的结构，这种结构使大量的DNA能够被装入很小的细胞体积中。问题是，这种包装阻止了DNA的使用。沉积在染色质组分上的表观遗传注释有助于包装和打开染色质。这些音符被一系列的酶复合物沉积、去除和解释。这些复合物是如何响应环境信号而受到调控的，目前还不是很清楚。我们发现其中一种酶复合物是由一种叫做PIP5K1A的酶调节的。为了响应环境信号，PIP5K1A产生一种叫做PIP2的小分子。我们的研究表明，PIP2粘附在酶复合体上，并控制它的工作方式。这导致沉积的表观遗传笔记发生变化，并最终改变细胞的行为。通过这种方式，我们认为PIP2作为信使通知和控制酶复合物以响应环境的变化。在这个提议中，我们打算了解PIP2如何粘附和改变酶复合物的工作方式。这种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，我们想确切地找出PIP2是如何附着在这种蛋白质上的，以及这是否会改变酶复合物沉积表观遗传记录的效果。了解这一过程的分子细节很重要，因为它增加了我们对细胞如何对环境做出反应的基本理解。此外，沉积表观遗传笔记的酶复合物通常不能正常工作，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展。了解酶复合物是如何被控制的，将有助于我们设计出药物，改变这些复合物的工作方式，这可能有助于调节我们衰老的速度和对抗疾病的方式。

项目成果

Mechanisms of SARS-CoV-2 Inactivation Using UVC Laser Radiation.

• DOI: 10.1021/acsphotonics.3c00828
• 发表时间: 2024-01-17
• 期刊: ACS PHOTONICS
• 影响因子: 7
• 作者: Devitt, George;Johnson, Peter B.;Hanrahan, Niall;Lane, Simon I. R.;Vidale, Magdalena C.;Sheth, Bhavwanti;Allen, Joel D.;Humbert, Maria V.;Spalluto, Cosma M.;Herve, Rodolphe C.;Staples, Karl;West, Jonathan J.;Forster, Robert;Divecha, Nullin;McCormick, Christopher J.;Crispin, Max;Hempler, Nils;Malcolm, Graeme P. A.;Mahajan, Sumeet
• 通讯作者: Mahajan, Sumeet

PIP4K2B: Coupling GTP Sensing to PtdIns5P Levels to Regulate Tumorigenesis.

PIP4K2B：将 GTP 传感与 PtdIns5P 水平耦合以调节肿瘤发生。

• DOI: 10.1016/j.tibs.2016.04.003
• 发表时间: 2016
• 期刊: Trends in biochemical sciences
• 影响因子: 13.8
• 作者: Fiume R

Phosphatidylinositol-5-Phosphate 4-Kinases Regulate Cellular Lipid Metabolism By Facilitating Autophagy.

• DOI: 10.1016/j.molcel.2018.03.037
• 发表时间: 2018-05-03
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Lundquist MR;Goncalves MD;Loughran RM;Possik E;Vijayaraghavan T;Yang A;Pauli C;Ravi A;Verma A;Yang Z;Johnson JL;Wong JCY;Ma Y;Hwang KS;Weinkove D;Divecha N;Asara JM;Elemento O;Rubin MA;Kimmelman AC;Pause A;Cantley LC;Emerling BM
• 通讯作者: Emerling BM

Exploring the controversial role of PI3K signalling in CD4+ regulatory T (T-Reg) cells.

• DOI: 10.1016/j.jbior.2020.100722
• 发表时间: 2020-04
• 期刊: Advances in biological regulation
• 作者: A. Poli;R. Fiume;S. Mongiorgi;A. Zaurito;B. Sheth;M. C. Vidalle;Shidqiyyah Abdul Hamid;Scott T. Kimber;F. Campagnoli;Stefano Ratti;Isabella Rusciano;I. Faenza;L. Manzoli;N. Divecha