Transcriptional Elongation Control in Development and Disease

项目摘要 在过去的二十年里，我的实验室的研究主要集中在分子的表征上 与伸长相关的因子和染色质修饰的功能和生化特性 RNA聚合酶II(POL II)的形式，以及它们的易位和突变如何与 儿童白血病和其他形式癌症的发病机制。我们的希望是我们的分子研究 在正常发育和癌症期间控制转录延长将促进我们的 了解重排白血病和其他形式人类白血病的分子机制 癌症是用来治疗这些恶性肿瘤的。 为此，我们在当前资金周期中进行的生化研究表明，超级延长 复合体、PAF1复合体和组蛋白H3K79甲基化机制是调节 由POL II暂停/释放。我们现在计划从分子上定义这一过程的基础，并确定其他 我们基因组中的细胞因子与SEC、PAF1和H3K79去甲基酶一起发挥调节作用 POL II的转录延伸。 我们将在多个模型系统中利用各种生化、分子和遗传工具来 解决这些目标，它们应该(I)有助于我们理解RNA的不同作用 聚合酶II延长因子在基因表达调控和发育分化中的作用； 和(Ii)对我们理解这个家族的突变和易位有根本性的影响 人类癌症的致癌因素。这些信息有可能被证明对试图 设计合理的癌症治疗方法。

Project Summary Studies from my laboratory during the past two decades have focused on the characterization of the molecular functions and biochemical properties of factors and chromatin modifications associated with the elongating form of RNA polymerase II (Pol II), and how their translocations and mutations are associated with the pathogenesis of childhood leukemia and other forms of cancer. Our hope is that our molecular studies of transcriptional elongation control during normal development and during cancer will advance our understanding of the molecular mechanisms of rearrangement-based leukemia and other forms of human cancer for the treatment of these malignancies. To this end, our biochemical studies during the current funding cycle demonstrated that the Super Elongation Complex, PAF1 complex, and histone H3K79 methylation machinery are central for the regulation of pause/release by Pol II. We now plan to molecularly define the basis of this process and to also identify other cellular factors within our genome functioning with SEC, PAF1, and the H3K79 demethylases to regulate transcription elongation by Pol II. We will take advantage of a variety of biochemical, molecular, and genetic tools in multiple model systems to address these aims, which should (i) be instrumental for our understanding of the diverse roles of RNA Polymerase II elongation factors in the regulation of gene expression and in development and differentiation; and (ii) have a fundamental impact on our understanding of the mutations and translocations of this family of factors in human cancer. This information has the potential of proving helpful to investigators attempting to design rational approaches for the treatment of cancer.