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Transcriptional regulatory networks in Drosophila development Human disease is frequently associated with aberrant signal transduction components, DNA-binding transcription factors and chromatin modifying enzymes, yet how these components form regulatory networks that generate specific biological outcomes is largely unknown. There is therefore a critical need to understand how regulatory proteins globally affect gene expression and cellular behavior. The long-term goal of my research is to identify predictive rules by which gene expression programs are regulated in an organism and apply them to human disease. It is known that gene expression programs are specified by signal transduction pathways that are activated by signals from neighboring cells during development. However, how these signal transduction pathways regulate gene expression is highly context-dependent. Based on current knowledge, context-dependent gene regulation depends on two principles, combinatorial regulation and (epigenetic) cellular memory. We are studying both principles in Drosophila using genome-wide techniques that map protein-DNA interaction, expression analysis, computational methods, and classical Drosophila genetics. Combinatorial gene regulation is the principle by which genes are activated or repressed by specific combinations of transcription factors under specific conditions. For example, transcription factors that are activated by mitogen-activated protein kinase (MAPK) signaling regulate very different gene expression programs dependent on the cell type. Presumably, this is because the binding and activity of these transcription factors depend on the combination of other transcription factors, signaling activities, and the cell-type specific chromatin environment. We would like to dissect the specificity of gene regulation of MAPK signaling in the early Drosophila embryo to understand the principles of combinatorial regulation. Cellular memory, the maintenance of cellular functions in the absence of the signal that initiated them, is fundamental for the development and maintenance of cell types in an organism. Most cell types are specified by multiple sequential signals during development and thus cells have to maintain a molecular memory of previous signals to be correctly specified and to maintain this state. This also means that if we had a number of molecular markers for cellular memory, we could better trace a cell's developmental history and use this information to predict its response to extracellular signals. One of the current projects is to investigate the role of Pol II stalling in cellular memory. Selected
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Zeitlinger
Lab