NSF Award
0818118
Intellectual merit <br/><br/>Chromosome dynamics are important not only for such basic cellular processes as proper segregation during mitosis and recombination during meiosis, but for gene regulation as well. Localized DNA sequences have been identified that mediate large-scale regulation involving a chromosomal region, a complex genetic locus, or an entire chromosome. Examples include X-inactivation and locus control in mammals, and dosage compensation and master regulatory gene function in the fruit fly, Drosophila melanogaster. Such regulation has been shown to be critically important for proper gene expression during development. Despite much progress in recent years in illuminating some of the underlying mechanisms, fundamental questions remain as to how regulatory proteins binding at localized sites produce global regulation. The project consists of two main parts. The first deals with the locus control elements that flank the Drosophila even skipped (eve) locus. These elements mediate positive regulation with locus-wide effects on early gene expression, in that the relevant enhancers are spread throughout the locus. The second deals with regulatory DNA at the 3' edge of the eve locus that causes trans-gene homing, in which exogenously introduced genes containing the eve promoter respond to endogenous eve enhancers from as far away as 120 kilobase pairs, "across" several other genes. The main thrust of each part will be to determine how long-range chromosome interactions change with changes in the DNA elements that mediate these activities, allowing development and testing of specific mechanistic models. In each case, the focus is on analyses that are feasible with established techniques, that provide fundamentally important information, and that take advantage of unique features of our model system, of which there are several. In addition to highly detailed knowledge of the eve regulatory DNA, it is possible to make fully functional transgenic copies of the entire locus. This will allow us to go beyond cataloguing correlations between chromosome dynamics and gene regulation, to test the functional significance of the observed changes. Thus, our analysis will lead to a greater understanding of mechanisms that regulate both chromosome dynamics and expression of the eve locus, and how the two are interrelated. The results of our studies will have important implications for how these processes are integrated for many other genes. This goal represents a major remaining frontier in the quest to learn how the genome directs the development and behavior of multicellular organisms, and their interactions with the environment. <br/><br/>Broader impacts<br/><br/>I. Students are strongly encouraged to participate. Both graduate and undergraduate students have earned authorship on recent publications from the laboratory. Post-doctoral associates receive training that prepares them to pursue independent research in the future. In each of these categories, women and minorities are highly represented.<br/><br/>II. The work provides exciting, current examples that are incorporated into lectures for graduate students, as well as presentations in a Community Outreach Program. These activities advance discovery and understanding while promoting teaching, training, and learning. <br/><br/>III. The results of the work are disseminated broadly through presentations at research conferences as well as in scientific publications. Aspects of previous work by the investigators have also been included in a number of college textbooks in recent years.<br/><br/>IV. Funding of this project will facilitate an established Outreach Program. K-12 student participation generates increased excitement about biological sciences, and encourages consideration of scientific career options. Teacher training is included. Under-represented groups with respect to economic status and race are largely those served in the Philadelphia, PA and Camden, NJ school districts, the target institutions of this program. This program has reached thousands of students and dozens of teachers over the past 3 years.
