The Arnosti laboratory studies gene regulation in the context of development. A main focus of our laboratory’s research has been understanding the “cis regulatory grammar” by which combinations of transcription factor binding sites in regulatory regions provide precise outputs for genes regulated in tissue- and temporal-specific patterns. A second related area concerns transcriptional repressors and corepressors, which are key contributors to this regulation. Our research has provided novel insights into biochemical and genetic pathways regulated by these factors. The powerful genetics and molecular biology of Drosophila allows us to test the importance of cis- and trans-acting regulators of transcription in a developmental setting. This fundamental research is critical for understanding the central regulatory mechanisms in biology, including in development, disease, and evolution.
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Main concepts in gene regulation that have stemmed from our research include:
1. Transcriptional enhancers function as “billboards”, allowing a flexible display of regulatory potential from different surfaces of bound activators and repressors.
2. Long- and short-range repression mechanisms represent fundamentally different ways in which the cell deploys chromatin-modifying machinery to achieve either very tightly targeted, acute impacts on enhancers, or widespread blanket suppression of regulatory information.
3. Cis-regulatory grammar of binding sites can be revealed by deep perturbation analysis of enhancers in vivo, combined with mathematical (fractional occupancy) modeling to reveal potential biochemical parameters – in essence, a prediction of how transcription factors “feel about” binding in an enhancer, next to other factors.
4. Transcriptional repressors play key roles in generating patterned gene expression in development, but they also are critical modulators of widely expressed genes that do not show a complete on/off regulation. This “soft repression” represents an essential layer of regulatory control that has been poorly investigated, for historical and technical reasons.