Atypical patterns of circadian clock gene expression in human peripheral blood mononuclear cells

Circadian ( approximately 24 h) rhythms in physiology and behaviour are observed in all mammals, including humans. These rhythms are generated by circadian clocks located in the hypothalamus and also in most peripheral tissues. Clock genes are essential components of circadian clocks, and mutations or polymorphisms within several of them have been associated with circadian disorders in humans. However, information about human clock gene expression has remained very limited. Peripheral blood mononuclear cells (PBMCs) represent an ideal material to investigate non-invasively the human clock at the molecular level. In the present study, we analysed the expression of three key clock genes, PER2, BMAL1 and REV-ERBalpha in PBMCs from ten healthy humans over a 24-h cycle. PER2 and BMAL1 were found to oscillate throughout the light-dark cycle in all subjects. Interestingly, despite normal melatonin and cortisol secretion patterns, two groups of subjects could be distinguished with significantly different mean PER2 and BMAL1 acrophases. BMAL1 oscillated with approximately the same phase as PER2, instead of being anti-phasic as anticipated from data previously obtained in other peripheral tissues. Furthermore, this unusual phase relationship of PER2 and BMAL1 in human PBMCs was associated with a constant expression of REV-ERBalpha, a crucial regulator of BMAL1, which is highly rhythmic in many other systems. These results reveal the existence of different chronotypes of clock gene expression patterns and suggest specific regulatory mechanisms in human PBMCs.