Sequence Requirements for Protein-Based Genetic Elements

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One of the most fundamental questions in biology is how organisms store and pass on genetic information. Research in the growing field of epigenetics has demonstrated that genetic information is not always encoded within an organism's DNA sequence. The discovery of yeast prions showed that changes in protein structure can be used to transmit genetic information. The formation of yeast prions involves the conversion of soluble proteins into an insoluble amyloid form. The amyloid form can be stably passed from mother to daughter cell, allowing the encoded epigenetic information to be passed on as a protein-based genetic element. This project examines the hypothesis that such structural conversions represent a common epigenetic mechanism of cellular regulation and inheritance in eukaryotes. A combination of in vitro and in vivo assays will be employed to define the sequence features that allow certain proteins to undergo prion-like structural conversions. This information will then be used to identify novel proteins whose activities are regulated by prion-like structural conversions. Taken together, these studies will advance our understanding of the role of such structural conversions in eukaryotic regulation and inheritance.Broader Impacts: In addition to the intellectual merit, this project has three major areas of broader impact. First, much of the research will be conducted in the context of a novel laboratory course, which is designed to be a hybrid of independent research and traditional laboratory classes. This course will allow students to generate new, publishable research, but in a sufficiently structured setting to allow for training of a large number of students. The course is designed to offer a diverse interdisciplinary training experience in biochemistry, molecular biology, genetics and bioinformatics. Second, as yeast are safe and inexpensive to work with, they provide an excellent system for teaching basic concepts of biochemistry and genetics to younger ages. Therefore, aspects of the research will be used in an elementary school outreach project called "Biochemistry is Elementary." This project introduces students to the scientific process and to basic concepts in biochemistry using exciting, hands-on activities. Finally, this work involves the development of novel technologies for the quantitative monitoring of prion dynamics, which will have applications for future research into regulatory prions and for industrial applications of amyloid fibrils.