Epigenetic factors regulate RNA polymerase II transcription Trypanosoma brucei

描述(申请人提供)：布鲁氏锥虫是一种单细胞原生动物寄生虫，感染非洲部分地区的人和牛。感染布氏毛滴虫的人患有一种名为非洲昏睡病的严重神经系统疾病，如果不治疗，这种疾病会在不经意间致命。针对这种寄生虫的化疗药物很少，毒性相对较大，而且在后勤上难以管理。因此，迫切需要确定新的药物靶点并开发更好的药物。这项提议将确定布鲁氏毛滴虫基因调控的独特方面，发现作为潜在药物靶点的新机制。与其他真核生物不同，锥体中由RNA聚合酶II(POL II)转录的基因作为长的初级RNA排列在大的多顺反子转录单位(PTU)中。对转录起始或终止的调控知之甚少。然而，最近的证据表明，表观遗传因素，特别是碱基J，一种高度修饰的核苷酸，在Pol II的调节中发挥着重要作用 中介转录。我们已经确定了转录起始的调控以及调控转录终止的证据。我提出了两个目的来研究这些压抑模式和其中涉及的表观遗传机制。

DESCRIPTION (provided by applicant): Trypanosoma brucei is a single cell protozoan parasite that infects humans and cattle in parts of Africa. Humans infected with T. brucei suffer from a severe neurological disease called African sleeping sickness that is inadvertently fatal when left untreated. Chemotherapeutic drugs against this parasite are few, relatively toxic, and logistically difficult to administer. The need to identify new drug targets and develop better medications is therefore urgent. This proposal will identify unique aspects of gene regulation in T. brucei, discovering novel mechanisms as potential drug targets. Unlike other eukaryotes, genes transcribed by RNA polymerase II (Pol II) in trypanosomes are arranged in large polycistronic transcription units (PTU) as long primary RNAs. Little is known about regulation of transcription initiation or termination. However, recent evidence indicates that epigenetic factors and especially base J, a hyper-modified nucleotide plays a significant role in regulation of Pol II mediated transcription. We have identified regulation of transcription initiation as well as evidence of regulated transcription termination. I propose two aims to study these modes of repression and the epigenetic mechanisms that are involved.