Project 451095

To know the molecular basis of disease is a daunting challenge. Knowing requires understanding of the processes that control how cells maintain, organize, and propagate their DNA complement - their genomes. We are investigating and defining these processes. In all cells of all eukaryotes, which include us, genes are organized within a spherical, membrane-enclosed compartment called the nucleus. The membrane shell that surrounds the genome is termed the nuclear envelope. Defects in the nuclear envelope are linked to multiple pathologies, such as muscular dystrophies, lipodystrophies, premature ageing, heart abnormalities, and cancer. Determining the underlying causes of these diseases requires an understanding of how the nuclear envelope functions, including its role in genome organization and the regulation of gene expression. To do this, we have taken advantage of the highly conserved structure and function of the nuclear envelope in species as diverse as humans and yeast. This has allowed us to conduct our studies in yeast where powerful genetic and biochemical approaches can be used. In recent years, we and others have begun to uncover how the nuclear envelope organizes chromatin and regulates gene expression. We have shown that structures present in the nuclear envelope can grab on to specific genes and, like puppeteers, alter their structure and turn them 'on' or 'off'. This proposal outlines state-of-the-art experiments designed to determine how interactions of genes with the nuclear envelope are maintained as the nucleus disassembles and reassembles during cell division, how this phenomenon contributes to the behavioral or environmental regulation of gene expression (epigenetics), and how a cellular regulatory pathway termed 'protein sumoylation' controls these events.