The body clock and metabolism
Circadian clocks rely on the master core transcription factors CLOCK and BMAL1 to drive rhythmic gene expression to ultimately regulate daily metabolism and physiology. To date, most studies have analysed oscillations of the transcriptome. However, since proteins are the true mediators of cellular functions, 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 tissues. Scientists utilised state-of-the-art mass spectrometry (MS) in combination with quantitative proteomics to investigate circadian rhythms in mammalian protein expression. Researchers discovered that approximately 6 % of the liver proteins cycled daily and their oscillations differed from those of their transcripts. This clearly indicated that post-transcriptional mechanisms critically shape the phase of rhythmic proteins and thus 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 circadian oscillations in phosphorylated proteins, a modification associated with protein function. Results showed that a large set of proteins in mouse liver displayed rhythms in their phosphorylation levels. Furthermore, scientists applayed MS to analyse protein complexes binding to clock DNA consensus sequences, and especially onto the promoter of the period circadian protein homolog 2 (per2) gene. They identified previously unknown interactors of BMAL and CLOCK that bind to consensus DNA sequences and appeared to have a role in chromatin modification. The work by the CLOCKPROTEOMICS study has emphasised the importance of the circadian clocks- by mean of protein abundance- in the regulation of mammalian metabolism. The researchers have provided firm evidences on the mechanism by which CLOCK/BMAL1 complexes regulate gene transcription.
Keywords
Body clock, metabolism, circadian oscillations, BMAL, CLOCK
