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Abstract

An open challenge in developmental biology is the prediction of gene expression patterns from knowledge of the spatiotemporal concentration dynamics of input transcription factors and their binding arrangement on regulatory DNA. Following successes in bacteria, most descriptions of transcriptional regulation in development have been built under the assumption of equilibrium, where no energy is expended during transcription factor binding or interaction with the transcriptional machinery. However, there is a mounting body of evidence that processes such as ATP expenditure for chromatin modification, the very short-lived binding times of transcription factors on DNA, and the dynamic nature of the general transcriptional machinery conspire to keep the system out of equilibrium. To put this widespread equilibrium assumption to a stringent test, we use the widely studied formation of the step-like gene expression pattern of hunchback mediated by the Bicoid activator and the pioneer transcription factor Zelda in the early embryo of the fruit fly Drosophila. Using a combination of quantitative single-cell live imaging, theoretical models, and computational simulations, we demonstrate that no equilibrium processes can recapitulate how Bicoid and Zelda dictate hunchback expression. Instead, we show that hunchback regulation can only be described by models where energy is expended in transcriptional regulation, which we speculate stems from the process of making chromatin accessible to transcription factors. Our results suggest that, in order to reach a predictive and quantitative understanding of cellular decision-making in development, the steps that operate outside of equilibrium in the transcriptional cascade, where energy is expended, need to be identified and characterized.