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bioRxiv · 10.1101/2025.09.04.674194

A scheduler for rhythmic gene expression

Gaidatzis, D.·Graf-Landua, M.·Methot, S.·Woelk, M.·Brancati, G.·Hauser, Y. P.·Meeuse, M.·Nahar, S.·Braun, K.·van der Does, M.·Aluri, S.·Kohler, H.·Smallwood, S.·Grosshans, H.
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Abstract

Genetic oscillators drive precisely timed gene expression, crucial for development and physiology. Using the C. elegans molting clock as a model, we investigate how oscillators can schedule the orderly expression of thousands of genes. Single cell RNA sequencing reveals a broad peak phase dispersion in individual issues, mirrored by rhythmic changes in chromatin accessibility at thousands of regulatory elements identified by time-resolved ATAC-seq. We develop a linear model to predict chromatin dynamics based on the binding of >200 transcription factors. This identifies nine key regulators acting additively to determine the peak phase and amplitude of each regulatory element. Strikingly, these factors can also generate constitutive, non-rhythmic activity through destructive interference. Validating its power, the model accurately predicts the impact of GRH-1/Grainyhead perturbation on both chromatin and transcript dynamics. This work provides a conceptual framework for understanding how combinatorial, non-cooperative transcription factor binding schedules complex gene expression patterns in development and other dynamic biological processes.

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Gaidatzis, D., Graf-Landua, M., Methot, S., Woelk, M., Brancati, G., Hauser, Y. P., Meeuse, M., Nahar, S., Braun, K., van der Does, M., Aluri, S., Kohler, H., Smallwood, S., Grosshans, H.. 2025-09-04. A scheduler for rhythmic gene expression. https://doi.org/10.1101/2025.09.04.674194

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