Grant: Operating Grant

Understanding the molecular basis for many acute and chronic diseases is a daunting challenge facing the biomedical community today. It is clear that comprehending processes that control cell growth and differentiation is central to this goal, and we strive to understand how gene expression controls these processes. Many factors contribute to controlling gene expression including the environment in which genes are stored. In every eukaryotic cell, including humans, genes are housed within a spherical, membrane-enclosed compartment, termed the nucleus. The membrane shell that surrounds the genome is termed the nuclear envelope (NE). In recent years it has become clear that the NE organizes chromatin and participants in defining how certain genes are controlled. We have shown that structures present in the NE can grab on to genes and, like puppeteers, they can alter their structure and, in this way, control whether a specific set of associated genes are turned on or off. Using state-of-the-art techniques, we are investigating how the interactions of genes with the NE are regulated and identifying the signals that control these events. As the NE is highly conserved in structure and function in eukaryotes as diverse as humans and yeast, these studies can be conducted in a yeast model system where powerful genetic and biochemical approaches can be used to investigate NE/chromatin interactions. It is clear that defects in NE proteins lead to diseases including heart abnormalities and cancer. Understanding their functions in nuclear organization will provide us with a critical understanding of the underlying causes of these diseases and provide an avenue for eventual rational intervention.