Grant: Operating Grant

Genome sequencing has begun to reveal the blueprints of life. The daunting challenge now facing the scientific community is to understand how genes are specifically and coordinately expressed to control cell growth and differentiation. The DNA in every eukaryotic cell is housed within a spherical, membrane-enclosed compartment, termed the nucleus. Cells have made use of this physical separation to control cellular function by regulating the passage of molecules into and out of the nucleus. The passage of molecules between the nucleus and cytoplasm is regulated by elaborate macromolecular gateways, termed nuclear pore complexes (NPCs). The NPCs control the access of proteins to the DNA, which, in turn, defines the amount and types of messenger RNAs that will be made in the cell, and thus the functions the cell will perform. In this proposal, we outline experiments to investigate how NPCs control transport into the nucleus at specific times during the growth and division of cells. In particular, we focus on understanding how the movement of molecules into the nucleus is controlled prior to and during mitosis, when copies of the DNA must be equally separated and distributed to the daughters. When this process is disrupted catastrophic consequences arise, including birth defects and cancer. In addition to controlling access of proteins to the genome, NPCs also directly interact with chromatin (structures containing the DNA). Recent evidence suggests that, like puppeteers, the NPCs can manipulate chromatin structure. Using state-of-the-art proteomic and genomic techniques, we are investigating how NPCs interact with factors that alter chromatin structure and how NPC assembly determines the structure of chromatin and the epigenetic regulation of gene expression. Defects in these processes are linked to the pathogenesis of a variety of disorders including Alzheimer's disease, type 1 diabetes, heart disease, and the metastatic potential of cancer cells.