Role of DNA localization in regulating transcription

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The subnuclear localization of DNA is highly regulated in all eukaryotes and has important but poorly understood effects on transcription and chromatin structure. The localization of DNA to the nuclear periphery has a clear role in establishing transcriptional repression (Fisher and Merkenschlager, 2002). My studies in Saccharomyces cerevisiae reveal that certain genes are also recruited to the nuclear periphery upon activation and that localization to the periphery promotes transcriptional activation (Brickner and Walter, 2004). Genome-wide studies in yeast indicate that many transcriptionally active genes localize at the nuclear periphery (Casolari et al., 2004). This phenomenon may be conserved between yeast and mammals; trancriptional activation of the _-globin locus in mice also occurs at the nuclear periphery (Ragoczy et al., 2006). My lab has extended these studies and we have discovered that gene recruitment to the nuclear periphery serves as a form of cellular memory of recent transcription, marking recently repressed genes to promote more rapid reactivation. The ultimate objective of this proposal is to understand two fundamental questions in cell biology: 1) how is the nucleus spatially organized and 2) how does this organization affect transcription? We will focus on the dynamic recruitment of the INO1 and GAL1 genes to the nuclear periphery in Saccharomyces cerevisiae. These are the best characterized examples of genes that undergo recruitment. Yeast offers a powerful combination of molecular genetics and biochemistry and will provide an ideal model system for studying this process. We will determine the molecular mechanisms used by cells to control the localization of genes. We will also define the generality, properties and molecular mechanism of transcriptional memory. Finally, we will test the functional role(s) of gene localization at the nuclear periphery.7.