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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：
8710047
负责人：
G Greg Wang
金额：
$ 24.15万
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：
2012-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8710047
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 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 screening stem cell population tumor tumorigenesis

项目摘要

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探讨肿瘤发生的表观遗传机制。Epigenetics 是由DNA序列非依赖性改变引起的表型变化的现象，例如染色质修饰文献记载了一系列的癌症失调，特别是干扰正常的组蛋白修饰。我们的重点是复发性染色体易位在人类白血病中发现，它靶向调节特定染色质修饰的分子参与者。在赖氨酸4处三甲基化的组蛋白H3（缩写为H3 K4 Me 3）。H3 K4 Me 3是一个重要的组蛋白标记与常染色质结构和活性转录相关。MLL，H3 K4 me 3特异性甲基转移酶是一个著名的白血病癌基因，MLL的功能获得性突变代表了是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NUP 98-JARID 1A破坏和/或赋予显性遗传，对H3 K4 Me 3特异性组蛋白去甲基化酶JARID 1的负面影响。因此，许多癌基因上的H3 K4 Me 3标记导致其反式激活。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最初是作为与肿瘤相互作用的因子分离的抑制基因RB。我们假设JARID 1家族的组蛋白去甲基化酶，在人类白血病中调节，属于一类新的白血病肿瘤抑制因子。在指导阶段，我将利用基因组方法来确定组蛋白甲基化与LSC和HSC相关的信号。此阶段的一个并行目标是建立靶向携带JARID 1A/1B失活等位基因的小鼠ES细胞，以及开发用于体外组蛋白酶学在独立阶段，我将检查JARID 1组蛋白的体内功能脱甲基酶在肿瘤抑制和/或正常发育中的作用。活性 JARID 1酶（以蛋白复合物的形式）及其介导的组蛋白体外去甲基化也将被描述。实验室提供的良好环境和补充培训计划大卫阿利斯博士（导师），沙欣拉菲博士（共同导师），合作者，和一个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调查员。独立阶段（3-5年级）的拟议研究将为我的未来铺平道路研究揭示肿瘤发生中的新表观遗传机制，并确定可药物化的靶点，新疗法。