Figure 5. Multi-level control of clock output and communication.

The clock can autonomously support a portion of circadian output. Nuclear receptors (NRs) regulate gene expression in tandem with clock proteins and are activated by extrinsic ligands, many of which oscillate in the bloodstream as a result of clock control in another tissue. The daily nuclear accumulation of certain transcription factors (TFs) is driven by feeding or body temperature rhythms. Systemic rhythms post-transcriptionally shape mRNA and protein oscillations. Feeding and fasting regulate RNA processing, translation and degradation while temperature fluctuations can induce alternative splicing programs that generate rhythmicity. Daily systemic energy metabolism regulates the functional status of proteins through post-translational modifications tied to metabolite levels. cAMP – cyclic adenosine monophosphate; NONO – non-POU domain-containing octamer-binding protein; SR – serine/arginine-rich splicing factor family; Ac – acetylation; P – phosphorylation.