Intellectual Merit: The ability of a cell to access genetic information embedded in the genome is essential for proper development; thus, it is of great importance to understand the cellular processes that guide proper gene regulation in vivo. The nucleosome, composed of a set of core histone proteins and DNA, is the basic building block of chromatin and acts as a primary scaffold for chromosome protection and compaction. Nucleosomes also act as barriers to restrict access to DNA and as a result can serve to prevent the expression of genes and consequently block cell division. Chromatin remodeling is a key step in the process of gene activation through disruptions of DNA-histone contacts that result in changes in DNA wrapping within nucleosomes, referred to as chromatin accessibility. Highly conserved from yeast to vertebrates, chromatin remodeling complexes (such as the SWI/SNF complex) function as essential cofactors to initiate gene transcription and assist in the regulation of transcription elongation as well as alternative splicing that produces different forms of the same gene. Fundamental questions needing to be resolved include how these complexes are targeted to genes in vivo and how they contribute mechanistically to both transcription activation and repression. Although generally acknowledged that chromatin structure can influence how gene transcripts are spliced to produce a variety of protein forms from the same gene, many assumptions are made and questions remain concerning the role of the nucleosome in vivo. This project tests the hypothesis that chromatin remodeling complexes contribute to gene repression through regulated remodeling of nucleosomes that normally act as impediments to transcription elongation at critical points in development. The research will address the in vivo functions of nucleosome remodeling complexes using biochemical assays of chromatin compaction, protein binding to chromatin and unique leading edge genetic tools developed for this research study. This project uses the fruitfly Drosophila melanogaster as a genetic model system to provide much needed and more detailed knowledge of the mechanisms by which chromatin remodeling complexes participate in programming gene expression during development. The results derived from this research are likely to have important and widespread implications for understanding the roles of the chromosome building blocks in gene regulation, as well as the remodeling enzyme complexes that control how that genome information is accessed by other factors, including the regulation of RNA polymerase elongation and alternative splicing in diverse systems.

Broader Impacts: The broader impacts of this project include (1) providing opportunities for high school, undergraduate and graduate (both MS and PhD) students to directly participate in mentored research, and (2) widespread dissemination of the results of this research through invited seminars and presentations at national meetings. Specifically, this research project will seek to actively recruit and train students from traditionally underrepresented minority groups, including local high school students from the Maywood (IL) and greater Chicago area, as well as college undergraduate students. Trainees will be mentored in basic research and assigned non-trivial roles on the project. Multidisciplinary training and education are vital to prepare students for diverse science careers; therefore, students are encouraged to think creatively and, in order to function effectively in the laboratory, they are taught developmental biology, genetics, scientific techniques, molecular/cellular biology and biochemistry. Students are also taught how to read and evaluate scientific literature, they are encouraged to identify role models to enforce their educational objectives, and to train them to give clear presentations, they attend and present at lab meetings for faculty and other students. Students are also encouraged to present their work at regional and national meetings and also to collaborate with expert investigators outside the institution in diverse scientific fields to enhance their multidisciplinary training experience. Within the institution, this work represents the only eukaryotic model system utilizing developmental genetics, and graduate lectures incorporate aspects of the work from the lab.

National Science Foundation (NSF)
Division of Molecular and Cellular Biosciences (MCB)
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Karen C. Cone
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Loyola University Stritch School of Medicine
United States
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