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: 8526811
• 负责人: G Greg Wang
• 金额: $ 24.9万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526811
• 关键词: Accounting; Adopted; Advisory Committees; Affect; Alleles; Cancer Patient; Cancerous; Cells; ChIP-seq; 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; stem cell population; tumor; tumorigenesis

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 ¿sigatures¿ 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.

我的长期研究兴趣是研究肿瘤发生的表观遗传机制。表观遗传学 是一种由 DNA 序列无关的改变引起的表型变化的现象，例如 染色质修饰。文献记录了一系列出现的癌症性放松管制 专门干扰正确的组蛋白修饰。我们的重点是复发性染色体易位 在人类白血病中发现，其目标是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 H3K4Me3）。 H3K4Me3 是一个突出的组蛋白标记 与常染色质结构和活性转录有关。 MLL，H3K4me3 特定的 甲基转移酶是著名的白血病癌基因，MLL的功能获得性突变代表 人类白血病中最常见的畸变之一。根据这些观察，我们最近 研究表明，白血病易位 NUP98-JARID1A 会破坏和/或赋予显性基因 对 H3K4Me3 特异性组蛋白去甲基化酶 JARID1 的负面影响。结果，异常积累 许多癌基因上的 H3K4Me3 标记导致它们的反式激活。我们的初步数据还 表明这种新颖的表观遗传机制可将正常造血干细胞（HSC）转化为 白血病起始干细胞（LSC）。 JARID1A 最初被分离为与肿瘤相互作用的因子 抑制器 RB。我们假设 JARID1 家族组蛋白去甲基化酶，在 在人类白血病中受到调节，属于白血病中的一类新型肿瘤抑制因子。 在指导阶段，我将利用基因组方法来识别组蛋白甲基化 与 LSC 和 HSC 相关的“签名”。此阶段的一个并行目标是建立 靶向含有 JARID1A/1B 失活等位基因的小鼠 ES 细胞，并开​​发用于 体外组蛋白酶学。在独立阶段，我将检查JARID1组蛋白的体内功能 使用基因敲除小鼠模型去甲基化酶在肿瘤抑制和/或正常发育中的作用。积极的 JARID1 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也将 被表征。实验室提供优良的环境和配套的培训项目 David Allis 博士（导师）、Shahin Rafii 博士（共同导师）、合作者和咨询委员会将 促进我在指导阶段的研究，并确保顺利过渡到独立研究者。 独立阶段（第3-5年）拟议的研究将为我的未来铺平道路 研究揭示肿瘤发生中新的表观遗传机制并确定“可成药”靶标 新疗法。