Understanding Complex Genome Editing and RNA Biology in Oxytricha

项目摘要 PI的实验室研究微生物真核生物中的自然基因组编辑系统，带来了强大的分子和 理解基因组进化和多样性的机械论方法。令人惊讶的老练 微生物真核生物DNA和RNA加工的变异表现出广泛的基因组结构 和遗传系统。一些途径侵蚀了基因的概念(例如，打乱的基因和RNA编辑) 甚至是孟德尔式的遗传，提醒我们，基因组草图序列可能与知识相去甚远 它的产品。基因组重排发生在不同的生物体中，并导致许多人类疾病， 尤其是癌症--一种基因组疾病，但程序化DNA重排的极端水平 纤毛虫Oxytricha发育所需使其成为研究基因组重塑的理想模式系统 以及RNA在协调这一过程中的作用。拟议的研究将扩大实验室对 这一非凡自然现象的分子机制和演化。今后五年的奋斗目标 包括了解DNA N6-腺嘌呤甲基化(6 MA)在发育和 重排，以及小的和长的非编码RNA与其相关的RNA之间的相互作用- 结合蛋白，以及重排的基因组。来自分子遗传学、生物化学和 染色质生物学为功能研究提供了平台，而比较基因组学则提供了对 杂乱基因组和复杂遗传结构的进化起源，解决了基本的 在开发过程中如何执行程序化重新安排以及这个过程是如何产生的问题 在进化过程中。

Project Summary The PI’s lab studies natural genome editing systems in microbial eukaryotes, bringing a strongly molecular and mechanistic approach to understanding genome evolution and diversity. The surprisingly sophisticated variations on DNA and RNA processing in microbial eukaryotes display a wide range of genome architectures and genetic systems. Some pathways erode the notions of a gene (e.g. scrambled genes and RNA editing) and even Mendelian inheritance, reminding us that a draft genome sequence can be a far cry from knowledge of its products. Genome rearrangements occur in diverse organisms, and contribute to many human diseases, especially cancer—a disease of the genome, but the extreme level of programmed DNA rearrangements required for development in the ciliate Oxytricha make it an ideal model system to study genome remodeling and the roles of RNA in orchestrating this process. The proposed research will expand the lab’s focus on the molecular mechanisms and evolution of this remarkable natural phenomenon. Goals for the next five years include understanding the roles of DNA N6-adenine methylation (6mA) during development and rearrangement, and the interactions between small and long noncoding RNAs and their associated RNA- binding proteins, together with the rearranging genome. Tools from molecular genetics, biochemistry, and chromatin biology provide the platform for functional studies, while comparative genomics offers insight into the evolutionary origins of scrambled genomes and complex genetic architectures, addressing the fundamental questions of how programmed rearrangements are executed during development and how this process arose during evolution.