This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).
As cells specialize to form diverse tissues during development of multicellular organisms, they activate batteries of genes responsible for the cell type-specific functions. Moreover, this process of coordinated gene activity is not merely a result of cell specialization, but also a guiding force behind determination of the cell's fate. Accordingly, a mechanism exists which contains activation of cell type-specific genes to the proper cell lineages and prevents their ubiquitous expression in other tissues. This mechanism operates with certain chromosome regions that contain clusters of cell type-specific genes, but molecular aspects of such regulation have not been elucidated. However, it becomes evident that packaging of the chromosomes within the nucleus plays a key role. In particular, cell type-specific tethering of certain chromosome regions to the nuclear envelope is associated with silencing of the genes embedded in these regions. This silencing is probably associated with modifications of the DNA-associated histone proteins which alter accessibility of genes to the transcription machinery. This research project is focused on understanding of the mechanism by which the major protein component of nuclear envelope, Lamin B, regulates silencing of nuclear envelope-tethered gene clusters through histone modifications. Animal model system such as the fruitfly Drosophila melanogaster is essential in this research because ablation of Lamin B-dependent mechanism(s) in Drosophila does not kill cells right away, unlike in mammals. Therefore, in Drosophila the Lamin B-mediated gene repression system can be dissected through modulation of its components, using the vast array of existing genetic models. Mechanisms that regulate cell type-specific gene clusters appear to be well conserved, therefore research findings using Drosophila will be applicable to other animals in which such studies are not feasible or practical.
This project will significantly contribute to general knowledge of regulation of gene expression and will strongly advance mechanistic understanding of development and cell differentiation. The studies capitalize on the lab's experience in molecular genetics, molecular biology, and genomics, and will provide broad laboratory training in cutting-edge techniques to graduate and undergraduate students with a special emphasis on involving minority undergraduate students in active laboratory research. Young aspiring scientists will receive educational benefit of personal involvement in new discoveries, and will have opportunities to disseminate their exciting findings through presentations at scientific meetings and publications in peer-reviewed journals. Such training and accomplishments will strongly foster their interest in basic research and provide a tremendous boost to their future careers in science.
