New circadian timer?

There may be more driving circadian rhythms -- the daily cycles that mediate countless behavioral and physiological processes in living organisms -- than cyclical gene expression, as previously believed. A biochemical pathway in green algae and human red blood cells appears to maintain its own 24-hour cycle without the guidance of transcription, according to two studies published online today (January 26) in Nature.

Image: Wikimedia commons, Luis Miguel Bugallo Sánchez

"The findings are interesting and provocative," molecular biologist linkurl:Isaac Edery;http://lifesci.rutgers.edu/%7Emolbiosci/faculty/edery.html of Rutgers University, who did not participate in the study, told The Scientist in an email. "What they show is that it is possible to drive a circadian rhythm in a molecular event in the absence of cyclical transcription or even transcription itself."Over the years, research in a variety of organisms has hinted at the existence of posttranscriptional clock regulators, but the molecular details remained undiscovered. Then, in 2005, a group of researchers in Japan identified one such system in prokaryotic cyanobacteria, demonstrating that certain proteins could maintain circadian oscillations after transcription and translation were inhibited, and that the oscillations could be reconstituted in vitro even without transcriptional cues. Still, the field was hesitant to deviate from the accepted transcriptional models of circadian clocks, said linkurl:Akhilesh Reddy,;http://www.neuroscience.cam.ac.uk/directory/profile.php?abreddy a neuroscientist at the University of Cambridge. "At that time, people thought this is in one photosynthetic bug. There's no way anything more complex is going to have this mechanism."To investigate this question, Reddy and his postdoc John O'Neill decided to study human red blood cells (RBC). Because mature RBC are largely devoid of organelles (including nuclei), they are naturally transcription-free, making them an ideal system to search for non-transcriptional circadian regulators. After some trial and error, the duo finally identified a class of enzymes that seemed to maintain 24-hour rhythms in RBC cultured under constant conditions and with no external cues, such as light.The enzymes, known as peroxiredoxins (PRX), help control the level of harmful reactive oxygen species (ROS) by undergoing oxidation when ROS accumulate. This reaction changes the structure of PRX in a way that can be easily detected by researchers. Monitoring the cells for this structural change, Reddy and O'Neill examined the oxidation patterns of the PRX enzymes. They found that the PRX enzymes were oxidized and reduced on a 24-hour cycle in the transcriptionless RBC. Furthermore, these rhythms could be tuned to environmental stimuli and did not fluctuate with changes in temperature -- two key features of circadian regulators.The PRX is "a readout of the metabolic activity of the cell," said molecular biologist and clinical endocrinologist linkurl:Joe Bass;http://www.cgm.northwestern.edu/cgm/Faculty-Research/Faculty/Joseph-Bass of Northwestern University, who was not involved in the research, "and [it] displays properties of the clock that are independent of transcription."Knowing that PRX enzymes were relatively conserved among eukaryotes, Reddy and O'Neill teamed up with other colleagues to ask the same question of a distantly related species -- a single-celled green algae called Ostreococcus tauri. In addition to having a relatively simple transcriptional clock, the researchers knew that keeping the algae in the dark suspends gene transcription. As in RBC, PRX structures still oscillated on a 24-hour cycle even in the absence of transcription. "The fact that we find the same marker rhythmic from the algae to humans is a very good indication that it is widespread, if not universal," said linkurl:Andrew Millar,;http://millar.bio.ed.ac.uk/ a systems biologist at the University of Edinburgh and an author on the algae study. Identifying such a ubiquitous mechanism may overturn years of thinking about the evolution of circadian clocks, he added. The transcription factors involved in clock regulation vary greatly between taxa, suggesting that while the general mechanism may be similar among species, the components are different. "Our view of the evolution of the clock was that it appeared to be an example, quite a neat example, of convergent evolution," he said. "These two papers fundamentally change that view. It now appears possible that clocks represent divergent evolution from a common ancestral mechanism."It's important to note, however, that while PRX oxidation appears to have a circadian cycle, it may not be a core regulator driving the 24-hour rhythms of the cell, said Millar. In other words, "PRX may just be the hands of the clock, not the cogs." More research is needed to get at the true mechanism of the non-transcriptional regulator, he added.Furthermore, the identification of non-transcriptional circadian oscillators does not relegate the transcriptional methods obsolete, noted Bass, who wrote an accompanying News & Views in Nature. These studies "demonstrated that in fact you can recapitulate features of a circadian oscillator in the absence of gene transcription, but I don't think that obviates that most oscillators are programmed by this genetic mechanism," he said. "The challenge is to understand the coupling between these processes.""We know too little about it, but I would definitely expect that the two clock mechanisms will be coupled," Millar agreed. Still, the identification of non-transcriptional circadian components is exciting and unexpected. "I myself have worked for 20 years on the transcriptional regulation of circadian clocks," he said. "The last thing that I expected to be working on now was a non-transcriptional oscillator."J.S. O'Neill and A.B. Reddy, "Circadian clocks in human red blood cells," Nature, 469:498-503, 2011.J.S. O'Neill, et al., "Circadian rhythms persist without transcription," Nature, 469:554-8, 2011.
**__Related stories:__***linkurl:New compound disrupts clock;http://www.the-scientist.com/news/display/57861/
[14th December 2010]*linkurl:Clock affects RNA splicing;http://www.the-scientist.com/news/display/57755/
[20th October 2010]*linkurl:No circ. clock for reindeer?;http://www.the-scientist.com/blog/display/57213/
[11th March 2010]

New circadian timer?

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