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

• 批准号: 8136726
• 负责人: G Greg Wang
• 金额: $ 3.53万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8136726
• 关键词: Accounting; Adopted; Advisory Committees; Affect; Alleles; Cancer Patient; Cancerous; Cells; Chemicals; Chimeric Proteins; Chromatin; Chromatin Structure; Chromosomal translocation; Clinical Trials; Collection; Complex; DNA; DNA Fingerprinting; DNA Methylation; DNA Sequence; Data; Development; Dominant-Negative Mutation; Down-Regulation; Ensure; Environment; Enzymatic Biochemistry; Enzymes; Epigenetic Process; Euchromatin; Family; Future; Gene Activation; Gene Expression; Gene Mutation; Gene Rearrangement; Genetic Transcription; Genomics; Goals; Grant; Growth; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Histone Deacetylase Inhibitor; Histone H3; Histones; Human; Human Pathology; In Vitro; Investigation; KDM5B gene; Knockout Mice; Laboratories; Lead; Light; Literature; Lysine; Malignant Neoplasms; Mediating; Mentors; Methylation; Methyltransferase; MicroRNAs; Modeling; Molecular; Molecular Target; Mus; Mutation; Myeloid Leukemia; Myeloproliferative disease; NUP98 gene; Normal tissue morphology; Oncogene Proteins; Oncogenes; Oncogenic; Pathway interactions; Phase; Play; Prevention; Proteins; Recurrence; Regulation; Research; Research Personnel; Role; Screening procedure; Stem cells; Structure; Techniques; Technology; Testing; Therapeutic; Therapeutic Intervention; Training Programs; Transactivation; Transcriptional Regulation; Tumor Suppression; Tumor Suppressor Proteins; base; cancer cell; cancer diagnosis; cancer stem cell; cancer therapy; cancer type; chromatin modification; clinically significant; demethylation; design; embryonic stem cell; gain of function; gain of function mutation; genome-wide; histone methyltransferase; histone modification; in vivo; inhibitor/antagonist; interest; leukemia; leukemia/lymphoma; leukemic stem cell; loss of function; metaplastic cell transformation; mouse model; new therapeutic target; novel; novel therapeutic intervention; programs; protein complex; public health relevance; stem cell population; tumor; tumorigenesis

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(申请人提供)：我的长期研究兴趣是研究肿瘤发生的表观遗传学机制。表观遗传学是一种由DNA序列无关的改变引起的表型改变的现象，如染色质修饰。这些文献记录了一系列癌症的去调控，它们似乎特别干扰了适当的组蛋白修饰。我们的重点是在人类白血病中发现的经常性染色体易位，它的目标是调节特定染色质修饰的分子玩家-组蛋白H3在赖氨酸4三甲基化(缩写为H3K4me3)。H3K4me3是一个显著的组蛋白标志，与常染色质结构和活跃的转录相关。MLL是一种H3K4me3特异性甲基转移酶，是一种著名的白血病癌基因，其功能获得突变是人类白血病最常见的突变之一。与这些观察结果一致，我们最近的研究表明，白血病易位NUP98-JARID1A干扰和/或赋予H3K4me3特异性组蛋白去甲基酶JARID1显性负效应。因此，H3K4me3标记在一些癌基因上的异常积累导致了它们的反式激活。我们的初步数据还表明，这种新的表观遗传机制将正常的造血干细胞(HSCs)转化为白血病启动干细胞(LSCs)。JARID1A最初是作为与肿瘤抑制因子Rb相互作用的因子而被分离出来的。我们推测，在人类白血病中表达下调的JARID1家族组蛋白去甲基酶属于白血病中一类新的肿瘤抑制因子。 在指导阶段，我将利用基因组学方法来鉴定与LSCs和HSCs相关的组蛋白甲基化“签名”。这一阶段的一个平行目标是建立含有JARID1A/1B失活等位基因的靶向小鼠ES细胞，以及开发体外组蛋白酶学技术。在独立阶段，我将使用基因敲除小鼠模型研究JARID1组蛋白去甲基酶在肿瘤抑制和/或正常发育中的体内功能。活性的JARID1酶(以蛋白质复合体的形式)及其在体外介导组蛋白去甲基化也将被表征。David Allis博士(导师)、Shahin Rafii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人员。在独立阶段(3-5年)拟议的研究将为启动我未来的研究铺平道路，以揭示肿瘤发生中的新表观遗传学机制，并确定新疗法的“可用药”靶点。 与公共卫生相关：表观遗传学是一种表型变化的现象，这种变化发生在一种称为组蛋白的特定类型的DNA相关蛋白上。表观遗传机制在调节基因表达和确定细胞状态方面发挥着关键作用，也有助于人类病理学的发生和发展，如癌症。在这个项目中，我们将重点放在某些类型的白血病上，这些白血病在人类血癌患者中占很大比例。然而，这些病例目前是无法治愈的。研究受影响的组蛋白修饰酶在肿瘤预防中的作用将有助于揭示新的致癌机制。它对癌症的诊断和治疗也具有临床意义。这项研究建立的体外酶学在未来可以用于其他癌症替代的研究，也可以用于筛选小分子抑制剂。例如，一种治疗想法是靶向癌细胞中不需要的“过度活跃”的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物的可行靶标。总之，研究表观遗传调控的分子基础将有助于更好地了解正常组织和/或肿瘤的发展，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。