Circadian rhythms, which have a periodicity of ~24 hours, regulate many physiological and metabolic processes. From algae to humans, circadian rhythms are regulated by a transcription-translation feedback loop. The products of clock genes are transcriptional activators that drive the expression of repressor genes, whose products feed back to inhibit the activators (see Bass and Takahashi). O’Neill and Reddy investigated a role for nontranscriptional control of circadian rhythms in human red blood cells (RBCs), which lack nuclei and cannot support transcription. The authors monitored peroxiredoxins, proteins that protect RBCs from peroxides by becoming oxidized and forming dimers, which are then reduced to the monomeric form. The authors found that peroxiredoxins exhibited a circadian redox rhythm in RBCs kept in the dark at constant temperature. This cycle could be entrained by temperature and was not affected by inhibitors of transcription or translation. The equilibrium between dimeric hemoglobin (a source of peroxide) and tetrameric hemoglobin (which produces less peroxide) also exhibited a circadian rhythm, as did the reducing agents NADH and NADPH. The redox cycle of peroxiredoxins in mouse NIH 3T3 cells also exhibited a circadian rhythm, and this was altered in cells from mice deficient in clock genes. Conversely, knockdown of various peroxiredoxin-encoding genes in human cells had effects on circadian gene expression. In an accompanying study, O’Neill et al. examined circadian rhythms in the simple alga Ostreococcus tauri. When kept at constant temperature in the dark, circadian rhythms in the alga that are controlled by transcription-translation loops are suspended until it is reexposed to light. However, the cycles continue from the point at which darkness occurred, rather than becoming reset. The authors found that redox cycles of peroxiredoxins in the alga persisted in the dark in a transcription-independent manner and that inhibitors of clocks in mammalian cells had similar effects in the alga. Together, these studies suggest that nontranscriptional metabolic cycles couple with genetic oscillators to control rhythmic outputs.
J. S. O’Neill, A. B. Reddy, Circadian clocks in human red blood cells. Nature 469, 498–503 (2011). [Online Journal]
J. S. O’Neill, G. van Ooijen, L. E. Dixon, C. Troein, F. Corellou, F.-Y. Bouget, A. B. Reddy, A. J. Millar, Circadian rhythms persist without transcription in a eukaryote. Nature 469, 554–558 (2011). [Online Journal]
J. Bass, J. S. Takahashi, Redox redux. Nature 469, 476–478 (2011). [Online Journal]