Post-transcriptional glucocorticoid receptor signalling synchronises circadian rhythms (human TT-seq)

Glucocorticoid (GC) hormones are vital for synchronising cellular clocks, aligning them with external day/night cycles, but mechanistic understanding is incomplete. We use a glucocorticoid receptor KO/rescue approach to show that residue E755 and the N-terminal intrinsically disordered region are essential for GC synchronisation, whereas nuclear translocation from the cytoplasm is not.

Using nascent and mature transcriptomics with (phospho)proteomics we show that, under physiological GC increases, the GR regulates a substantial proportion of gene expression post-transcriptionally. Rapid upregulation of Per1 mRNA occurs through increased RNA processing not synthesis, which drives GC synchronisation via acute increases in nascent PER1 and not PER2 protein. We find synchronisation to a single GC dose is highly heterogeneous between individual cells.