The body clock and metabolism

Circadian oscillations rely on the master proteins CLOCK and BMAL1 to drive rhythmic gene expression implicated in certain biological functions under circadian control. To date, most studies have analysed oscillations of the transcriptome. However, since proteins are the true mediators of cellular function, scientists need to re-evaluate their approach and extend their work at the proteomic level.

The EU-funded 'Circadian clock function by quantitative proteomics and phosphoproteomics' (CLOCKPROTEOMICS) project looked at the role of proteins in circadian clock function in mouse tissue. Scientists utilised state-of-the-art mass spectrometry in combination with quantitative proteomics to investigate circadian rhythms in mammalian protein expression.

Researchers discovered that approximately 6 % of the liver proteins are cycled daily and their oscillations differ from those of their transcripts. This clearly indicated that post-transcriptional mechanisms are the ones that drive the phase of rhythmic proteins and metabolic processes.

The circadian oscillations of liver proteins seem to be instrumental, not only for metabolism, but for other cellular processes. The next step in the project was to describe the circadian oscillations in phosphorylated proteins, a modification associated with enhanced protein function. Results showed circadian oscillations in the phosphorylation levels of liver proteins.

Furthermore, scientists analysed which protein complexes bind to clock DNA consensus sequences, and especially onto the promoter of the period circadian protein homolog 2 (per2) gene. They identified additional proteins in addition to BMAL and CLOCK that bind to consensus DNA sequences and described for the first time a role of clock proteins in chromatin modification.

The work by the CLOCKPROTEOMICS study has emphasised the importance of the circadian clock in mammalian metabolism. The researchers haveprovided a firm knowledge platform on the mechanism by which CLOCK proteins regulate gene transcription.