If modules are defined as densely interconnected networks with sparse external connections, it follows that interaction between modules is limited -- a property referred to as 'insulation'. But there are biological systems, such as the yeast Environmental Stress Response (ESR), in which stimulation of distinct signaling pathways leads to both signal-specific outcomes and others that are generic -- that is, common to many different signals. Systems such as the ESR raise the question of how signaling pathways can interact at common promoters without activating inappropriate stimulus-specific promoters. In other words, how are modules connected to a common response while otherwise remaining insulated from each other? In the case of the ESR, induction in response to different stresses depends on different transcription factors, demonstrating that the convergence of these signaling pathways does not occur upstream of a common transcription factor. Thus, these genes act as 'OR' gates for a number of signaling pathways, pointing to chromatin structure as one of the few possible remaining steps at which signal integration may occur. We are developing techniques for the high-resolution study of chromatin structure, to use in the study of promoters of ESR genes. We will examine the chromatin structure and histone modification state of these promoters upon induction by a variety of stresses. Data from these studies will be analyzed to attempt to discern general rules for the effects of chromatin environment on gene expression. In addition to adding to the understanding of connections between modules, a greater understanding of chromatin's influence on gene expression will be of great clinical benefit, as it is becoming increasingly clear that misregulation of chromatin structure and modification state is central to a number of important disease processes, including a number of types of cancer.

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National Institute of General Medical Sciences (NIGMS)
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Harvard University
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