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：
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
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/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

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研究表观遗传学中的表观科学机制。是由DNA序列非依赖性改变引起的表型变化的现象染色质修饰。专门干扰适当的组蛋白修饰。在人类白血病中发现，该白血病针对调节特定染色质修饰的分子参与者。组蛋白H3三甲基化在赖氨酸4（缩写为H3K4me3）。与白染料结构和主动转录相关甲基转移酶是一种著名的白血病癌基因，MLL的功能性突变代表人类白血病中最常见的畸变之一。研究表明，白血病易位NUP98-JARID1A破坏和/或赋予主导对H3K4me3特异性组蛋白脱甲基的负面影响。 H3K4me3在我们的交易中标记了我们的预售数据。表明这种新型的表观遗传机制转化了正常造血干细胞（HSC）白血病发射干细胞（LSC）最初是与肿瘤相互作用的因素 Supressor RB。在人类白血病中受到调节，属于白血病中新型的肿瘤支持者。在指导阶段，我愿意鉴定组蛋白甲基化的基因组方法挥之不去sigatures¿与LSC和HSC相关的。靶向小鼠ES细胞tharbor Jarid1a/1b灭活等位基因，以开发用于IN的技术体外组蛋白酶学，在独立阶段，我将检查JARID1组蛋白的体内功能使用敲除小鼠模型中的肿瘤替代酶和/或正常发育 JARID1酶（以蛋白质复合物的形式）及其介导的组蛋白在体外也将表征出色的环境和互补的培训计划 David Allis博士（导师），Shahin Rafii博士（Co-Incertor），合作者和咨询委员会的促进我在指导的分阶段阶段的研究，并确保向独立研究者的平稳过渡。独立阶段的支撑研究（3-5年）将铺平蟾蜍来启动我的未来研究以揭示肿瘤发生中新型的表观遗传机制并识别–可吸毒的目标新颖的治疗学。