The regulatory DNA that controls transcription harbors natural sequence variants at multiple DNA length scales, from single nucleotide polymorphisms to large scale structural variants. Given that changes in gene regulation are critical in development, disease and evolution, a central challenge is to understand how sequence variants at all of these scales impact proximal molecular phenotypes and downstream organismal phenotypes. I will present our work probing the molecular mechanisms that govern transcription in the developing Drosophila embryo, with a view to understanding how regulatory DNA can drive precise gene expression patterns while the underlying sequence is quite plastic. I will discuss examples at different levels of complexity, from single enhancers to entire developmental loci, and emphasize how coupling quantitative measurements to computational models can decipher underlying principles of transcription.
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