Circadian rhythms persist without transcription in a eukaryote

Abstract

Circadian rhythms are ubiquitous in eukaryotes, and co-ordinate numerous aspects of behaviour, physiology and metabolism, from sleep/wake cycles in mammals to growth and photosynthesis in plants1,2. This daily timekeeping is thought to be driven by transcriptional/translational feedback loops, whereby rhythmic expression of clock gene products regulates expression of associated genes in approximately 24-hour cycles. The specific transcriptional components differ between phylogenetic kingdoms3. The unicellular pico-eukaryotic alga, Ostreococcus tauri, possesses a naturally minimised clock, which includes many features that are shared with higher eukaryotes (plants), such as a central negative feedback loop that involves the morning-expressed CCA1 and evening-expressed TOC1 genes4. Given that recent observations in animals and plants have revealed prominent post-translational contributions to timekeeping5, a reappraisal of the transcriptional contribution to oscillator function is overdue. Here we show that non-transcriptional mechanisms are sufficient to sustain circadian timekeeping in the eukaryotic lineage, though they normally function in conjunction with transcriptional components. We identify oxidation of peroxiredoxin proteins as a transcription-independent rhythmic biomarker, which is also rhythmic in mammals6. Moreover we show that pharmacological modulators of the mammalian clockwork have the same effects on rhythms in Ostreococcus. Post-translational mechanisms, and at least one rhythmic marker, appear to be better conserved than transcriptional clock regulators. It is plausible that the oldest oscillator components are non-transcriptional in nature, as in cyanobacteria7, and are conserved across kingdoms.

Circadian transcriptional regulation by the posttranslational oscillator without de novo clock gene expression in Synechococcus

“…4). The coordination of the posttranslational oscillator and the transcription/translation feedback loops has recently also been suggested to occur in the mammalian (8) and Ostreococcus circadian systems (9). In both cases, transcription/ translation feedback loops regulated by transcription-related proteins (such as the CLOCK and BMAL proteins in mammals and the CCA1 and TOC1 proteins in Ostreococcus) are important in driving the transcriptional rhythms.…”

“…In both cases, transcription/ translation feedback loops regulated by transcription-related proteins (such as the CLOCK and BMAL proteins in mammals and the CCA1 and TOC1 proteins in Ostreococcus) are important in driving the transcriptional rhythms. They are probably coupled to posttranslational oscillators driving the rhythmic oxidation/oligomerization of PRX, which is sustained without de novo transcription/translation (8,9). It is noteworthy that the Ostreococcus circadian system, in particular, shares some important properties with that of Synechococcus: (i) high-amplitude transcription cycles are observed under LL; (ii) general transcription activity, including the de novo expression of known clock genes, is strongly inhibited in the dark; and (iii) some posttranslational oscillations are sustained to keep time under DD, so that the phase of the transcriptional rhythms can be adjusted after light returns (3,8).…”

“…In eukaryotic model organisms, the core process that generates and maintains self-sustaining circadian oscillations is reported to be driven by transcription/translation feedback loops (7). However, it was recently demonstrated in the pico-eukaryotic alga Ostreococcus tauri and human red blood cells that the oxidation of 2-Cys peroxiredoxin (PRX) proteins undergo ≈24-h modification cycles without transcription (8,9). Therefore, we now require a more general understanding of the mechanisms by which posttranslational oscillators control overt physiological rhythms, such as transcription cycles.…”

Unwinding the differences of the mammalian PERIOD clock proteins from crystal structure to cellular function

“…The daily regulated expression of mBMAL1 is ensured by a stabilizing feedback loop, in which the heme binding nuclear receptor REV-ERBα/β represses mBMAL1 expression, whereas ROR-α/β activates it (1,2). Recently, nontranscriptional circadian oscillations of peroxiredoxin oxidation-reduction, hemoglobin dimer-tetramer transitions, and NADH/NADPH oscillations have been described in human red blood cells, which are interconnected with the transcriptional feedback loops in nucleated cells (3,4).…”

Rythmes du vivant : des horloges pour tous les temps

“…Plusieurs observations montrent que d'autres mécanismes, qui ne sont pas fondés sur une régula-tion de l'expression génétique, peuvent également être à l'origine de rythmes circadiens. Ces observations ont tout d'abord porté sur les cyanobactéries, et viennent d'être étendues aux érythrocytes humains [6] ainsi qu'à l'algue Ostreococcus tauri [7].…”