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Oliver RandoWe are applying whole-genome approaches to studying epigenetic phenomena, such as the effect of chromatin environment on the process of transcription. Traditional methods of chromatin structure determination typically yield base-pair-resolution information on the translational positioning of single nucleosomes, or poorer-resolution data on histone modification states of the histones associated with a particular stretch of DNA. We have used genomic DNA microarrays to measure nucleosome position and modification state over large segments of the genome, and are using this information to study mechanisms of chromatin remodeling in yeast, to probe the higher-order structure of chromatin in vivo, and to formulate general rules for how chromatin environment influences gene expression. We also plan to develop a screen for unstably heritable transcriptional phenotypes in yeast. Genes located within a few kilobases of yeast telomeres are known to be repressed in a variegated fashion. This repression is heritable, but the repressed state of the subtelomeric gene can be lost in an apparently stochastic manner. The lack of repression then becomes heritable, until the state of repression switches back again. We will screen for other yeast states that are unstably heritable, characterize the kinetic constants for switching of repression at many of these loci, and screen for mutations that change these rates. Using this information, we hope to understand the machinery involved in the maintenance and switching of epigenetic states, and to probe, under selective pressure, the utility of having multiple distinct states in an isogenic population. Contact |
