Genome binding/occupancy profiling by high throughput sequencing Expression profiling by high throughput sequencing
Summary
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. The model accurately predicts the impact of GRH-1/Grainyhead perturbation on both chromatin and transcript dynamics, validating its power. This work provides a powerful 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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