In the nucleus, genomic DNA is packaged into nucleosomes, the fundamental packaging unit. Nucleosomal DNA is further condensed into higher order chromatin structures that are not well understood. Presently, our research is centered on Heterochromatin protein 1, HP1, that plays a central role in the formation of higher order chromatin structure and gene expression. One project is focused on mechanisms of gene silencing by HP1 using the fruit fly as a model system. We are determining the effects of tethering HP1 upstream of reporter genes that can be analyzed for changes in chromatin structure and gene expression. We are also examining the role of HP1 in metastasis using human breast cancer cells as a model system. This project grew out of a collaboration with Dr. Dawn Kirschmann of the laboratory of Dr. Mary Hendrix (Northwestern University). HP1 is significantly down regulated in highly/invasive metastatic breast cancer cells, compared with poorly invasive/non-metastatic breast cancer cells. Experiments are underway to identify genes regulated by HP1 through microarray and chromatin immunoprecipitation analyses. These data will shed light on the role of HP1 as a potential metastatsis suppressor. Last, we have iundertaken a project to determine the role of nuclear envelope associated proteins in genome organization and gene expression. This project is in collaboration with the laboratory of Pamela Geyer (Biochemistry, University of Iowa). We are currently focusing on the role of lamins, intermediate filmament proteins, that line the inner nuclear envelope, providing structural support for the nucleus and making contacts with chromatin. In humans, mutation in lamins causes a number of diseases such as Emery-Dreifuss muscular dystrophy and Hutchinson-Gilford progeria (early onset aging) that are collectively known as laminopathies. We are using Drosophila as a model to determine the function of A-type lamins in gene expression and development. Our studies will provide insights on the molecular defects associated with laminopathies in humans.