Interplay between circadian and other transcription factors—Implications for cycling transcriptome reprogramming

Circadian transcription factors (TFs) orchestrate daily rhythms in gene expression to drive rhythmic biological functions. In mammals, this system relies on the TF CLOCK:BMAL1, which binds E-boxes to initiate rhythmic transcription. While traditionally viewed as a master activator, CLOCK:BMAL1 is now recognized to engage in additional regulatory functions that are essential for its activity. This perspective focuses on the mammalian circadian clock and integrates genomic, structural, and single-molecule footprinting data to highlight emerging insights into how CLOCK:BMAL1 regulates chromatin architecture, cooperates with other TFs, and coordinates complex enhancer dynamics. We propose an updated framework for how circadian TFs operate within dynamic and multifactorial chromatin landscapes, and prime cis-regulatory elements for rhythmic transcriptional bursts. We also discuss how this framework underlies circadian reprogramming and transcriptional plasticity.