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My overall interest is to study global regulatory networks in the bacterium E. coli, an organism that is amenable to genetic and biochemical approaches. We study two different problems, each of which illuminates this issue from different perspectives. Our study of the heat shock response has led us into a consideration of how the cell monitors and regulates the folding state of proteins, how proteins are targeted for degradation and how the cytoplasmic and periplasmic compartments in E. coli are coordinated. Our study of transcriptional regulatory networks has led us to dissect the functional anatomy of RNA polymerase and to establish a genomics approach to discover the connections between different networks.