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

• 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

'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.

人体所有细胞中都存在“组蛋白脱乙酰基酶”（HDAC）酶。它们的功能是“关闭”基因，并确保它们保持“脱离”。在许多方面，关闭基因的关闭与打开基因一样重要。 HDAC酶代表了令人兴奋的医疗机会，因为它们是“可毒品”的。诊所中抑制HDAC活性的药物已经被用作抗癌药，并且在实验室中，对其对痴呆和抗炎特性的有益作用。因此，为了评估其作为药理目标的潜力，有一种引人注目的应用和学术动机来研究其生理作用。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。一旦确定它们的形状，它就可以使我们了解HDAC与其他蛋白质和小分子（例如肌醇磷酸盐（IP））结合的方式。我们最近在体外表明（即在试管中）表明，HDAC的酶活性取决于IP的结合。从这个发现之后，该项目的目的是了解IP对细胞和小鼠中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水平，中和高水平的细胞，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，形成多蛋白的“复合物”。对IP的存在最敏感的复合物称为MIDAC，它由三个结合在一起的蛋白（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射线晶体学解决MIDAC的结构。 3）MIDAC在细胞中的作用是完全未知的，因此我们使用缺少复合物的三个成员DNTTIP1的细胞来表征MIDAC的生理活性。通过了解HDAC复合功能的分子基础，我们可以使用该知识来设计新药来防止它们起作用。阻止HDAC无法工作的能力对包括上型疾病，双极分散疾病和阿尔茨海默氏病的广泛疾病具有有益的影响，使其成为极好的药物靶标。

项目成果

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