Transcriptional Elongation Control in Development and Disease

项目摘要 在过去的二十年里，我的实验室的研究集中在分子的表征上， 因子的功能和生化特性以及与延伸相关的染色质修饰 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的癌症的发病机制。我们希望我们的分子研究 在正常发育和癌症期间的转录延伸控制将促进我们的研究。 了解基于复发的白血病和其他形式的人类白血病的分子机制， 用于治疗这些恶性肿瘤。 为此，我们在当前资助周期内的生化研究表明， 复合物、PAF 1复合物和组蛋白H3 K79甲基化机制是调节细胞凋亡的核心。 Pol II暂停/释放。我们现在计划从分子上确定这一过程的基础，并确定其他 我们基因组中的细胞因子与SEC、PAF 1和H3 K79脱甲基酶一起发挥作用， Pol II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， 解决这些目标，这应该（i）有助于我们理解RNA的不同作用 聚合酶II延伸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产生了根本性的影响。 人类癌症的因素。这一信息有可能证明有助于调查人员试图 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.