Understanding the contribution of inositol phosphate signalling to class-1 HDAC complex function

了解磷酸肌醇信号传导对 1 类 HDAC 复合体功能的贡献

基本信息

批准号：
BB/N002954/1
负责人：
Shaun Cowley
金额：
$ 64.72万
依托单位：
University of Leicester
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%2FN002954%2F1
关键词：
Understanding contribution inositol phosphate signalling

项目摘要

'Histone deacetylase' (HDAC) enzymes are present in all cells of the body. Their function is to switch genes 'off', and make sure they stay 'off'. In many respects shutting a gene down is every bit as important as switching a gene on. HDAC enzymes represent an exciting medical opportunity because they are 'druggable'. Already, drugs which inhibit HDAC activity are being used in the clinic as anti-cancer agents, and in the laboratory for their beneficial effects on dementia and anti-inflammatory properties. There is therefore a compelling applied, as well as academic, motivation for studying their physiological roles in order to assess their potential as pharmacological targets. We use a technique called 'X-ray crystallography' which allows us to determine the shape and structure of HDAC enzymes at a molecular level. Once we have determined their shape it allows us to understand the way that HDACs bind to other proteins and small molecules such as inositol phosphate (IP). We recently showed in vitro (i.e. in a test tube) that the enzymatic activity of HDACs was dependent upon the binding of IP. Following on from this discovery, the purpose of this project is to understand the importance of IP to HDAC function in cells and in mice. To do this we have three main objectives: 1) We plan to generate cells with low, medium and high levels of IP and test whether these correlate with level of HDAC activity. 2) In cells, HDACs interact with other proteins to form a multi-protein 'complex'. The complex most sensitive to the presence of IP is called, MIDAC and it consists of three proteins bound together (HDAC1, DNTTIP1 and MIDEAS). To understand the regulation of HDAC complexes by IP we plan to solve the structure of MIDAC using X-ray crystallography. 3) The role of MIDAC in cells is completely unknown and so we aim characterize the physiological activity of MIDAC, using cells lacking one of the three members of the complex, DNTTIP1. By understanding the molecular basis of HDAC complex function we can use that knowledge to design new drugs to prevent them from working. The ability to stop HDACs from working has beneficial effects on a wide-range of diseases, including epiplepsy, bipolar dissorder and Alzheimer's disease, making them excellent drug targets.

“组蛋白脱乙酰酶”(HDAC) 酶存在于身体的所有细胞中。它们的功能是“关闭”基因，并确保它们保持“关闭”状态。在许多方面，关闭基因与开启基因同样重要。 HDAC 酶代表了一个令人兴奋的医疗机会，因为它们是“可成药的”。抑制 HDAC 活性的药物已经在临床上用作抗癌药物，并在实验室中因其对痴呆和抗炎特性的有益作用而被使用。因此，研究它们的生理作用以评估它们作为药理学靶点的潜力具有令人信服的应用和学术动机。我们使用一种称为“X 射线晶体学”的技术，该技术使我们能够在分子水平上确定 HDAC 酶的形状和结构。一旦我们确定了它们的形状，我们就可以了解 HDAC 与其他蛋白质和小分子（例如磷酸肌醇 (IP)）结合的方式。我们最近在体外（即在试管中）证明 HDAC 的酶活性依赖于 IP 的结合。继这一发现之后，该项目的目的是了解 IP 对细胞和小鼠 HDAC 功能的重要性。为此，我们有三个主要目标：1) 我们计划生成具有低、中和高水平 IP 的细胞，并测试这些细胞是否与 HDAC 活性水平相关。 2) 在细胞中，HDAC 与其他蛋白质相互作用形成多蛋白质“复合物”。对 IP 的存在最敏感的复合物称为 MIDAC，它由结合在一起的三种蛋白质（HDAC1、DNTTIP1 和 MIDEAS）组成。为了了解 IP 对 HDAC 复合物的调节，我们计划使用 X 射线晶体学解析 MIDAC 的结构。 3) MIDAC 在细胞中的作用完全未知，因此我们的目标是使用缺乏复合物三个成员之一 DNTTIP1 的细胞来表征 MIDAC 的生理活性。通过了解 HDAC 复杂功能的分子基础，我们可以利用这些知识来设计新药以防止其发挥作用。阻止 HDAC 发挥作用的能力对多种疾病具有有益作用，包括癫痫、双相情感障碍和阿尔茨海默氏病，使其成为极好的药物靶点。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sin3A recruits Tet1 to the PAH1 domain via a highly conserved Sin3-Interaction Domain.

DOI：
10.1038/s41598-018-32942-w
发表时间：
2018-10-02
期刊：
Scientific reports
影响因子：
4.6
作者：
Chandru A;Bate N;Vuister GW;Cowley SM
通讯作者：
Cowley SM

Proximity-dependent biotin identification (BioID) reveals a dynamic LSD1-CoREST interactome during embryonic stem cell differentiation.

DOI：
10.1039/d1mo00236h
发表时间：
2022-01-17
期刊：
Molecular omics
影响因子：
2.9
作者：
Barnes CE;English DM;Broderick M;Collins MO;Cowley SM
通讯作者：
Cowley SM

Histone deacetylase (HDAC) 1 and 2 complexes regulate both histone acetylation and crotonylation in vivo.

DOI：
10.1038/s41598-018-32927-9
发表时间：
2018-10-02
期刊：
Scientific reports
影响因子：
4.6
作者：
Kelly RDW;Chandru A;Watson PJ;Song Y;Blades M;Robertson NS;Jamieson AG;Schwabe JWR;Cowley SM
通讯作者：
Cowley SM

Comprehensive Transcriptomic Analysis of Novel Class I HDAC Proteolysis Targeting Chimeras (PROTACs).

DOI：
10.1021/acs.biochem.2c00288
发表时间：
2023-02-07
期刊：
BIOCHEMISTRY
影响因子：
2.9
作者：
Baker, India M.;Smalley, Joshua P.;Sabat, Khadija A.;Hodgkinson, James T.;Cowley, Shaun M.
通讯作者：
Cowley, Shaun M.

Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors.

DOI：
10.1038/s41467-017-02242-4
发表时间：
2018-01-04
期刊：
Nature communications
影响因子：
16.6
作者：
Kalin JH;Wu M;Gomez AV;Song Y;Das J;Hayward D;Adejola N;Wu M;Panova I;Chung HJ;Kim E;Roberts HJ;Roberts JM;Prusevich P;Jeliazkov JR;Roy Burman SS;Fairall L;Milano C;Eroglu A;Proby CM;Dinkova-Kostova AT;Hancock WW;Gray JJ;Bradner JE;Valente S;Mai A;Anders NM;Rudek MA;Hu Y;Ryu B;Schwabe JWR;Mattevi A;Alani RM;Cole PA
通讯作者：
Cole PA