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We are interested in how 10 and 30 nm chromatin fibers fold into interphase and mitotic chromosomes, how interphase chromosomes are positioned within nuclei, and what this means for DNA functions such as transcription and replication. Currently, our understanding of these higher levels of chromatin organization, which we refer to as large-scale chromatin structure, is poor. We are using a novel combination of molecular biology, cell biology, genetics, and imaging tools to visualize folding dynamics of specific chromosome regions and individual gene loci, and to uncover the general folding motifs underlying interphase and mitotic chromosome structure.. Our long term goals are twofold: (1) to dissect the large-scale chromatin structure and dynamics of specific chromosome regions, to understand the functional significance of the changes which accompany transcription and replication, and to identify the cis and trans factors responsible for these changes in structure and (2) to determine the structural folding motifs which underlie interphase and metaphase chromosome architecture, to identify the cis and trans determinants of chromosome condensation, and finally to understand how these cis and trans determinants function to control large-scale chromatin condensation and decondensation. Eventually we would like to be able to apply our knowledge of chromosome dynamics to design improved tools for gene therapy and biotechnology.