Understanding the essential requirement for HDAC1 and HDAC2 in tissue development and homeostasis: implications for disease and therapy.

了解 HDAC1 和 HDAC2 在组织发育和稳态中的基本要求：对疾病和治疗的影响。

• 批准号: MR/J009202/1
• 负责人: Shaun Cowley
• 金额: $ 261.94万
• 依托单位: University of Leicester
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ009202%2F1
• 关键词: Understanding; essential; requirement; HDAC1; HDAC2

'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'. My lab studies how HDACs do this and which, amongst the 25,000 genes in each cell, are selected for inactivation. HDAC enzymes also 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 are being further developed 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 need an improved understanding of how individual HDAC enzymes work in normal cells. In this study we intend study two closely related HDAC enzymes, HDAC1 and HDAC2. One of the best methods for understanding how an enzyme works is to generate mutant cells in which the specific enzyme has been inactivated, or 'knocked-out'. These 'knock-out' cells can then be examined for changes in their characteristics, lack of growth for instance, which can then be attributed to the function of that particular enzyme. Previously, we have generated 'knock-out' cells for HDAC1 and HDAC2 alone, but their function is overlapping, and so the effects on cell growth were small. To get around this, we have generated cells in which HDAC1 and 2 can be removed at the same time, so called 'double knock-out' cells. Early experiments indicate that loss of both enzymes causes cells to die, indicating that their activity is essential. Using DNA technology it is possible to add back normal or mutated forms of HDAC1 to prevent the double knock-out cells from dying and then ask, which parts of the enzyme are important for its function? In related experiments, we also intend to visualize the actual molecular structure of HDAC1 bound to a molecule called MTA1, using a technique called X-ray crystallography. The interaction of HDAC1 with other molecules in the cell is fundamental to their function. By understanding the molecular basis of these interactions we can better understand how HDAC enzymes work in normal and cancer cells, and potentially use that knowledge to design new drugs to prevent them from working. The ability to stop HDAC1 and 2 from working, as seen in our double knock-out cells, causes cells to stop growing and die, making them excellent drug targets in the search for improved anti-cancer agents.

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”。我的实验室研究HDAC是如何执行此操作的，并且在每个细胞中的25,000个基因中被选中以失活。 HDAC酶也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，并且正在进一步开发其对痴呆和抗炎特性的有益作用。因此，有一个引人注目的应用，以及研究其生理角色的学术动机。为了评估其作为药理学靶标的潜力，我们需要对单个HDAC酶在正常细胞中的工作方式有了改进的了解。在这项研究中，我们打算研究两种密切相关的HDAC酶HDAC1和HDAC2。理解酶的工作原理的最佳方法之一是生成突变细胞，其中特定酶被灭活或“敲除”。然后可以检查这些“敲除”细胞的特征变化，例如缺乏生长，然后可以归因于该特定酶的功能。以前，我们仅针对HDAC1和HDAC2生成了“敲除”细胞，但是它们的功能是重叠的，因此对细胞生长的影响很小。为了解决这个问题，我们已经生成了可以同时删除HDAC1和2的单元，所谓的“双敲除”细胞。早期实验表明，这两种酶的丧失会导致细胞死亡，表明它们的活性至关重要。使用DNA技术，可以添加hDAC1的正常形式或突变形式，以防止双基因敲除细胞死亡，然后询问，该酶的哪些部分对其功能很重要？在相关实验中，我们还打算使用称为X射线晶体学的技术可视化与称为MTA1分子的HDAC1的实际分子结构。 HDAC1与细胞中其他分子的相互作用是其功能的基础。通过了解这些相互作用的分子基础，我们可以更好地了解HDAC酶在正常和癌细胞中的工作方式，并有可能利用这些知识来设计新药以防止它们起作用。如我们的双基因敲除细胞中所见，阻止HDAC1和2的工作能力使细胞停止生长和死亡，从而使它们成为寻求改善的抗癌剂的出色药物目标。

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

A 'click' chemistry approach to novel entinostat (MS-275) based class I histone deacetylase proteolysis targeting chimeras.

• DOI: 10.1039/d2md00199c
• 发表时间: 2022-12-14
• 期刊: RSC medicinal chemistry
• 影响因子: 4.1

Histone deacetylase (HDAC) 1 and 2 are essential for accurate cell division and the pluripotency of embryonic stem cells

• DOI: 10.1073/pnas.1321330111
• 发表时间: 2014-07-08
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Jamaladdin, Shereen;Kelly, Richard D. W.;Cowley, Shaun M.
• 通讯作者: Cowley, Shaun M.