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Cancer epigenetics: Understanding histone methylation in leukemia stem cells

癌症表观遗传学：了解白血病干细胞中的组蛋白甲基化

基本信息

批准号：
8455386
负责人：
G Greg Wang
金额：
$ 10.43万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8455386
关键词：
Cancer epigenetics Understanding histone methylation

项目摘要

DESCRIPTION (provided by applicant): My long-term research interest is to investigate epigenetic mechanisms in oncogenesis. Epigenetics is a phenomenon for phenotypic changes caused by DNA sequence-independent alterations such as chromatin modification. The literature has documented a collection of cancerous deregulations that appear specifically to interfere with proper histone modification. Our focus is recurrent chromosomal translocation found in human leukemia, which targets molecular players that regulate a specific chromatin modification- histone H3 tri-methylated at lysine 4 (abbreviated as H3K4Me3). H3K4Me3 is a prominent histone mark associated with euchromatin structure and active transcription. MLL, an H3K4me3-specific methyltransferase enzyme, is a famed leukemia oncogene, and gain-of-function mutation of MLL represents one of the most common aberrations in human leukemia. In keep with these observations, our recent studies demonstrate that a leukemic translocation NUP98-JARID1A disrupts and/or imparts dominant negative effect on H3K4Me3-specific histone demethylases JARID1. As a result, aberrant accumulation of H3K4Me3 marks on a number of oncogenes leads to their transactivation. Our preliminary data also suggests that such a novel epigenetic mechanism transforms normal hematopoietic stem cells (HSCs) to leukemia-initiating stem cells (LSCs). JARID1A was initially isolated as factor to interact with tumor suppressor RB. We hypothesize that JARID1 family histone demethylases, which were found down regulated among human leukemia, belong to a novel class of tumor suppressors in leukemias. During the mentored phase, I will utilize genomic approaches to identify the histone methylation "signatures" that are associated with LSCs and HSCs. A parallel objective in this phase is to establish targeted mouse ES cells that harbor JARID1A/1B inactivation alleles, as well as to develop techniques for in vitro histone enzymology. In the independent phase, I will examine in vivo functions of JARID1 histone demethylases in tumor suppression and/or normal development using knockout mouse models. Active JARID1 enzymes (in form of protein complexes) and their mediated histone demethylation in vitro will also be characterized. An excellent environment and complementary training program provided by laboratories of Dr. David Allis (mentor), Dr. Shahin Rafii (co-mentor), collaborators, and an Advisory Committee will facilitate my research in the mentored phase and ensure a smooth transition to an independent investigator. The proposed research at the independent phase (Year 3-5) will pave the road to launch my future investigation to reveal novel epigenetic mechanisms in oncogenesis and identify 'druggable' targets for novel therapeutics. PUBLIC HEALTH RELEVANCE: Epigenetics is a phenomenon of phenotypic changes caused by alterations that occur on a specific type of DNA-associated protein termed as histone. Epigenetic mechanisms play critical roles in regulating gene expression and defining cellular states, as well as contributing to the onset and development of human pathologies such as cancers. In this project, we focus on some types of leukemia that accounts for a large percentage of human blood cancer patients. However these cases are currently incurable. Investigating the role of affected histone modifier enzymes in tumor prevention will shed light on novel oncogenic mechanisms. It also has clinical significance for cancer diagnosis and therapies. In vitro enzymology established in the study can be adopted in the future for studies of other cancerous alternations and also for screening small molecular inhibitors. For example, one therapeutic idea is to target an unwanted 'hyperactive' histone methyltransferase activity in cancer cells. Importantly, many chromatin modifier enzymes are considered as feasible targets for screening inhibitor chemicals. In summary, studying the molecular basis of epigenetic regulation will promote greater understanding of the development of normal tissue and/or tumors, which in turn, helps to design some novel effective therapeutic intervention for human cancers.

描述（由申请人提供）：我的长期研究兴趣是调查肿瘤发生的表观遗传机制。表观遗传学是一种由DNA序列非依赖性改变（如染色质修饰）引起的表型变化现象。文献已经记录了一系列似乎专门干扰正确组蛋白修饰的癌性失调。我们的重点是在人类白血病中发现的复发性染色体易位，其靶向调节特定染色质修饰的分子参与者-组蛋白H3在赖氨酸4处三甲基化（缩写为H3 K4 Me 3）。H3 K4 Me 3是与常染色质结构和活性转录相关的突出的组蛋白标记。MLL是一种H3 K4 me 3特异性甲基转移酶，是一种著名的白血病癌基因，MLL的功能获得性突变是人类白血病中最常见的畸变之一。与这些观察结果一致，我们最近的研究表明，白血病易位NUP 98-JARID 1A破坏和/或赋予H3 K4 Me 3特异性组蛋白脱甲基酶JARID 1显性负效应。因此，H3 K4 Me 3标记在许多癌基因上的异常积累导致它们的反式激活。我们的初步数据还表明，这种新的表观遗传机制将正常造血干细胞（HSC）转化为白血病起始干细胞（LSC）。JARID 1A最初被分离为与肿瘤抑制因子RB相互作用的因子。我们假设，JARID 1家族组蛋白去甲基化酶，这是发现在人类白血病下调，属于一类新的肿瘤抑制剂在白血病。在指导阶段，我将利用基因组学方法来识别与LSC和HSC相关的组蛋白甲基化“签名”。在这一阶段的一个平行目标是建立有针对性的小鼠ES细胞，港口JARID 1A/1B失活等位基因，以及开发技术，在体外组蛋白酶学。在独立的阶段，我将研究在体内的功能JARID 1组蛋白去甲基化酶在肿瘤抑制和/或正常发展使用敲除小鼠模型。还将表征活性JARID 1酶（以蛋白质复合物的形式）及其介导的体外组蛋白去甲基化。由大卫·阿利斯博士（导师）、沙欣·拉菲博士（共同导师）、合作者和咨询委员会的实验室提供的良好环境和补充培训计划将促进我在导师阶段的研究，并确保顺利过渡到独立研究者。独立阶段（3-5年）的拟议研究将为我未来的研究铺平道路，以揭示肿瘤发生中的新表观遗传机制，并确定新疗法的“可药物化”靶点。公共卫生相关性：表观遗传学是一种表型变化的现象，这种变化是由一种特定类型的DNA相关蛋白（称为组蛋白）上发生的改变引起的。表观遗传机制在调节基因表达和定义细胞状态以及促进人类病理学如癌症的发生和发展方面起着关键作用。在这个项目中，我们专注于某些类型的白血病，占人类血癌患者的很大比例。然而，这些病例目前无法治愈。研究受影响的组蛋白修饰酶在肿瘤预防中的作用将揭示新的致癌机制。对肿瘤的诊断和治疗也有重要的临床意义。本研究建立的体外酶学可用于其他癌变的研究和小分子抑制剂的筛选。例如，一种治疗思路是靶向癌细胞中不需要的“过度活跃”组蛋白甲基转移酶活性。重要的是，许多染色质修饰酶被认为是筛选抑制剂化学品的可行靶标。总之，研究表观遗传调控的分子基础将促进对正常组织和/或肿瘤发展的更好理解，这反过来又有助于设计一些新的有效的人类癌症治疗干预措施。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

An Allosteric Interaction Links USP7 to Deubiquitination and Chromatin Targeting of UHRF1.

DOI：
10.1016/j.celrep.2015.07.046
发表时间：
2015-09-01
期刊：
Cell reports
影响因子：
8.8
作者：
Zhang ZM;Rothbart SB;Allison DF;Cai Q;Harrison JS;Li L;Wang Y;Strahl BD;Wang GG;Song J
通讯作者：
Song J

Multiple interactions recruit MLL1 and MLL1 fusion proteins to the HOXA9 locus in leukemogenesis.

DOI：
10.1016/j.molcel.2010.05.011
发表时间：
2010-06-25
期刊：
Molecular cell
影响因子：
16
作者：
Milne TA;Kim J;Wang GG;Stadler SC;Basrur V;Whitcomb SJ;Wang Z;Ruthenburg AJ;Elenitoba-Johnson KS;Roeder RG;Allis CD
通讯作者：
Allis CD

Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger.

DOI：
10.1038/nature08036
发表时间：
2009-06-11
期刊：
NATURE
影响因子：
64.8
作者：
Wang, Gang G.;Song, Jikui;Wang, Zhanxin;Dormann, Holger L.;Casadio, Fabio;Li, Haitao;Luo, Jun-Li;Patel, Dinshaw J.;Allis, C. David
通讯作者：
Allis, C. David

Tudor: a versatile family of histone methylation 'readers'.