Understanding the recruitment of Class I HDACs into diverse repression complexes: implications for physiological activity and therapeutic devlopment

了解 I 类 HDAC 招募到不同的抑制复合物中：对生理活动和治疗开发的影响

• 批准号: BB/J009598/1
• 负责人: Shaun Cowley
• 金额: $ 56.79万
• 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: 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=BB%2FJ009598%2F1
• 关键词: Understanding; recruitment; Class; HDACs; into

'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 intend to study how three different HDAC enzymes (HDACs 1, 2 and 3) work in normal cells. 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.

“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。我的实验室研究HDAC是如何做到这一点的，以及在每个细胞的25,000个基因中，哪些基因被选择去失活。HDAC酶也代表了一个令人兴奋的医疗机会，因为它们是“可药用的”。抑制HDAC活性的药物已经在临床上用作抗癌剂，并且正在进一步开发其对痴呆症和抗炎特性的有益作用。因此，有一个令人信服的应用，以及学术，动机研究其生理作用，以评估其作为药理学靶点的潜力。我们打算研究三种不同的HDAC酶（HDAC 1、2和3）如何在正常细胞中工作。了解酶如何工作的最好方法之一是产生突变细胞，其中特定的酶已经失活或“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，然后可以将其归因于该特定酶的功能。以前，我们已经单独产生了HDAC 1和HDAC 2的“敲除”细胞，但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，我们已经产生了可以同时去除HDAC 1和2的细胞，即所谓的“双敲除”细胞。早期的实验表明，这两种酶的缺失会导致细胞死亡，这表明它们的活性是必不可少的。使用DNA技术，可以添加正常或突变形式的HDAC 1，以防止双敲除细胞死亡，然后问，酶的哪些部分对其功能很重要？在相关的实验中，我们还打算使用一种称为X射线晶体学的技术来可视化HDAC 1与一种名为MTA 1的分子结合的实际分子结构。HDAC 1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酶在正常细胞和癌细胞中的工作方式，并可能利用这些知识来设计新的药物来阻止它们工作。正如我们的双敲除细胞中所看到的那样，阻止HDAC 1和2工作的能力导致细胞停止生长和死亡，使它们成为寻找改进的抗癌药物的绝佳药物靶点。

项目成果

Class I HDACs share a common mechanism of regulation by inositol phosphates.

• DOI: 10.1016/j.molcel.2013.05.020
• 发表时间: 2013-07-11
• 期刊: MOLECULAR CELL
• 影响因子: 16
• 作者: Millard, Christopher J.;Watson, Peter J.;Celardo, Ivana;Gordiyenko, Yuliya;Cowley, Shaun M.;Robinson, Carol V.;Fairall, Louise;Schwabe, John W. R.
• 通讯作者: Schwabe, John W. R.

Backbone resonance assignment of the BCL6-BTB/POZ domain.

• DOI: 10.1007/s12104-017-9778-z
• 发表时间: 2018-04
• 期刊: Biomolecular NMR assignments
• 影响因子: 0.9
• 作者: Lin LY;Evans SE;Fairall L;Schwabe JWR;Wagner SD;Muskett FW
• 通讯作者: Muskett FW

A specific mutation in TBL1XR1 causes Pierpont syndrome.

• DOI: 10.1136/jmedgenet-2015-103233
• 发表时间: 2016-05
• 期刊: Journal of medical genetics
• 影响因子: 4
• 作者: Heinen CA;Jongejan A;Watson PJ;Redeker B;Boelen A;Boudzovitch-Surovtseva O;Forzano F;Hordijk R;Kelley R;Olney AH;Pierpont ME;Schaefer GB;Stewart F;van Trotsenburg AS;Fliers E;Schwabe JW;Hennekam RC
• 通讯作者: Hennekam RC

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

Mutations in TBL1X Are Associated With Central Hypothyroidism.

TBL1X中的突变与中央甲状腺功能减退症有关。

• DOI: 10.1210/jc.2016-2531
• 发表时间: 2016-12
• 期刊: The Journal of clinical endocrinology and metabolism
• 作者: Heinen CA;Losekoot M;Sun Y;Watson PJ;Fairall L;Joustra SD;Zwaveling-Soonawala N;Oostdijk W;van den Akker EL;Alders M;Santen GW;van Rijn RR;Dreschler WA;Surovtseva OV;Biermasz NR;Hennekam RC;Wit JM;Schwabe JW;Boelen A;Fliers E;van Trotsenburg AS
• 通讯作者: van Trotsenburg AS