A direct role for cholesterol in the regulation of transcription

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In any given cell, only certain genes will be switched on (or expressed) and it is the specific combination of expressed genes that determines the type of cell (for example a muscle, skin or nerve cell). Thus, the control of gene expression lies at the heart of cellular identity. We have discovered a multi-protein complex that uses lipids to regulate genes. This is highly unusual because lipids are normally associated with cell membranes. Our hypothesis is that this complex uses lipids to form contacts with other factors within the cell nucleus and that this process is central to switching genes between an on and off state. Understanding how lipids regulate genes will provide important insights into the events that control the formation of different cell types and may also provide opportunities to use lipid-acting drugs to treat diseases that result from aberrant gene regulation.In this proposal we present evidence that the essential lipid cholesterol can play an active role in turning genes off. We find that cholesterol directs the formation of interactions between proteins on the DNA that then blocks expression of nearby genes. In this proposal we will determine the genes that are switched off by cholesterol. This will be achieved by blocking cholesterol production and then measuring gene expression and also by using mutant proteins that no longer bind to cholesterol. We will then determine how cholesterol changes the formation of protein complexes on the DNA and identify the critical proteins that are directing the action of the cholesterol switch. Finally, the effect of cholesterol on the activities of enzymes that alter gene expression will be tested. The outcomes of the proposal will enhance our understanding of the role of cholesterol in gene regulation and provide new insights into the function of lipids that are not associated with cellular membranes.