Post-transcriptional glucocorticoid receptor signalling synchronises circadian rhythms

Circadian rhythms are driven by cellular clocks throughout the body that maintain optimal health. Glucocorticoid (GC) hormones are vital for synchronising cellular clocks, aligning them with external day/night cycles, but the mechanism was unresolved. We use a glucocorticoid receptor (GR) KO/rescue approach to show that residue E755 and the N-terminal intrinsically disordered region are essential for GC synchronisation, whereas nuclear translocation is not. Using nascent and mature transcriptomics with (phospho)proteomics we find that physiological GC increases regulate many genes post-transcriptionally. Rapid upregulation of Per1 mRNA occurs through increased RNA processing not synthesis, and drives GC synchronisation by increasing in nascent PER1, not PER2 protein. Individual cellular clocks respond heterogeneously to a GC bolus, explaining how cell populations are entrained by daily systemic cues in vivo . Our findings provide mechanistic insight into hormonal nuclear receptor signalling and a cellular basis for how internal clocks are aligned with external day/night cycles.