1. Transcription and Development
Transcriptional regulation in the context of development poses challenging and important questions. We wish to elucidate the mechanisms of transcriptional switches to understand developmental regulation in Drosophila and to gain insights into general principles of eukaryotic gene regulation. Many aspects of development are crucially dependent upon transcriptional repression, a particular focus of interest for our lab. The complex patterns of gene expression in the early Drosophila embryo are critically dependent on short-range repressors such as Giant and Knirps, as well as long-range repressors such as Hairy. Co-repressors such as Groucho, CtBP, and Rpd3 interact with these proteins to silence target enhancers. We are developing molecular insights into the action of these proteins using transgenic approaches and chromatin immunoprecipitation studies in embryos. These studies describe the biological context in which repressors are integrated, providing a deeper understanding of the molecular basis of development.
2. Systems Biology and enhancer design: identification of a cis-regulatory grammar.
A popular model for transcriptional enhancers is the "enhanceosome" that features a highly constrained cis element design. Our analysis of short-range repressors on defined regulatory elements indicates that a second, more flexible form of design ("billboard" enhancer) better describes many developmental regulatory elements. Working with colleagues in the Quantitative Biology Initiative at MSU (biomodel.msu.edu), we are applying mathematical approaches to decode the 'grammar' of cis regulatory elements, as revealed by our analysis of transcriptional repressors in Drosophila. This work will lead to the development of powerful bioinformatics approaches to interpret cis regulatory genomic sequences.
3. Tumor Suppressor Proteins.
Retinoblastoma tumor suppressor proteins are important regulators of the cell cycle in vertebrates, and Drosophila Rbf proteins perform similar roles in the fly. In collaboration with the Henry lab (MSU) we have identified a novel interaction between Rbf proteins and the COP9 signalosome, a conserved regulatory complex that controls Rbf stability. We have found that regulated stability of retinoblastoma proteins plays a role in the developmental control of gene expression by this corepressor protein. Studies of the Rbf tumor suppressor in Drosophila will provide important insights on the function of this protein in vertebrates.