Understanding Complex Gene Editing Systems and RNA Biology in Oxytricha Project Summary/Abstract: The PI's lab studies novel genetic 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 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 and dependence on chromosomal rearrangements for correct development in the ciliate Oxytricha make it an ideal model system to study genome remodeling and the roles of RNA in epigenetic control of this process. The proposed research will focus on understanding the molecular mechanism and evolutionary origin of this remarkable phenomenon. Goals for the next five years include obtaining a more detailed understanding of the interactions between small and long noncoding RNAs, both with each other and together with the rearranging genome. Tools from molecular genetics, RNA biochemistry, and chromatin biology provide the platform for functional studies, while comparative genomics of closely and more distantly related species will provide insight into the evolutionary origins of scrambled genomes and complex genetic architectures in the Oxytricha lineage, addressing the basic questions of how they rearrange during development and how they arose during evolution.
to Public Health: Genome rewiring events, through translocations, deletions, and even massive chromosomal rearrangements (chromothripsis), contribute to genome instability associated with many human diseases, including a significant portion of cancers and inherited or spontaneous diseases. Furthermore, many classes of small and long noncoding RNAs participate in genome remodeling pathways or the maintenance of genome integrity, while aberrantly spliced RNA products that can template DNA recombination could increase the frequency of genome rearrangements, resulting in either deletion of tumor-suppressing genes, formation of chimeric genes, or duplication and subsequent over-expression of genes that promote tumor stability. Because of its magnitude of RNA-regulated genome rewiring events, Oxytricha is unparalleled as a model system to shed light on the complex events that regulate genome stability, and similar mechanisms that may contribute to cancer and genome instability in humans.
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|Lindblad, Kelsi A; Bracht, John R; Williams, April E et al. (2017) Thousands of RNA-cached copies of whole chromosomes are present in the ciliate Oxytricha during development. RNA 23:1200-1208
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