Cancer epigenetics: Understanding histone methylation in leukemia stem cells

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变化的现象，如 染色质修饰。这些文献记录了一系列出现的癌性放松管制 特别是为了干扰适当的组蛋白修饰。我们的重点是复发性染色体易位 在人类白血病中发现，它以调节特定染色质修饰的分子为靶点 组蛋白H3在赖氨酸4位三甲基化(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有关。MLL，一种H3K4me3特异性 甲基转移酶，是一种著名的白血病癌基因，MLL的功能获得突变代表 人类白血病中最常见的异常之一。与这些观察结果一致，我们最近 研究表明，白血病易位NUP98-JARID1A干扰和/或传递显性 对H3K4me3特异性组蛋白去甲基酶JARID1的负面影响。结果，异常积累的 一些癌基因上的H3K4me3标记会导致它们的反式激活。我们的初步数据也 提示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最初是作为与肿瘤相互作用的因子被分离出来的 抑制子Rb。我们推测JARID1家族的组蛋白去甲基酶 在人类白血病中调节，属于白血病中一类新的肿瘤抑制因子。 在指导阶段，我将利用基因组方法来鉴定组蛋白甲基化 与LSCs和HSCs相关联的签名。这一阶段的一个平行目标是建立 靶向携带JARID1A/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，我将研究JARID1组蛋白的体内功能 利用基因敲除小鼠模型研究肿瘤抑制和/或正常发育中的去甲基酶。主动型 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 被刻画出来。良好的环境和实验室提供的配套培训计划 David Allis博士(导师)、Shahin Rafii博士(共同导师)、合作者和咨询委员会将 在指导阶段为我的研究提供便利，并确保平稳过渡到独立调查人员。 在独立阶段(3-5年级)提出的研究将为我的未来铺平道路 揭示肿瘤发生中新的表观遗传机制并确定可用药靶点的研究 新的治疗方法。

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.