New circadian timer?

Researchers identify a metabolic pathway that appears to maintain its own 24-hour cycle, challenging the traditional view of a purely transcription-driven biological clock

By | January 26, 2011

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]

Comments

Avatar of: Dov Henis

Dov Henis

Posts: 97

January 27, 2011

Again And Again And Again:\n\nCircadian Schmircadian\n\n"Dispel Some Figments Of 2010 Science Imagination"\nhttp://pulse.yahoo.com/_2SF3CJJM5OU6T27OC4MFQSDYEU/blog/articles/245540\n\n"Sleep is inherent for life via the RNAs, the primal Earth ORGANISMS formed and active ONLY under direct sunlight in pre-metabolism genesis era."\n\n\nDov Henis\n(comments from 22nd century)
Avatar of: Dov Henis

Dov Henis

Posts: 97

January 28, 2011

Just located my following old posting:\n\nCircadian Rhythm: \nGenes Are Organisms, Not Molecular Contraptions \nHenis Dov\nJul 03, 2008 \nhttp://www.physorg.com/news116687712.html\n\n\nA. "Molecular Basis And Regulation Of Circadian Rhythms In Plants" \nhttp://www.eurekalert.org/pub_releases/2008-07/asop-pit062408.php\n\n\nB. A mechanisms of energy absorption, by which archae genes became and function as active energy packages, i.e. became living organisms: \nhttp://www.physorg.com/news115053032.html\n\n\nC. Chromosomes coil more tightly during the day and relax at night. \nhttp://www.physorg.com/news114872572.html\n\n\nD. My elsewhere suggestions re the origin of Circadian Rhythm applies neatly in the above cases. I posit that the mechanism involved in the absorption of energy by the archae genes is the mechanism of phasing of RNA-type olygomers into replicating primal Earth organisms, individual independent genes. This phasing from chemicals to living organisms was the genesis of Earth's biosphere. \n\nScience will comprehend one day that genes are primal and genomes are evolved, organisms. \n\nCircadian rhythm is an innate gene-genome characteristic, inborn-brought-about at the energetic conditions during the genesis of genes in the process of phasing from chemical olygomers to replicating life, to living genes which are base life energy packages. \n\nFor the archaic genes, parents of all Earth's Life, direct sunlight was the only source of energy, and it was available to them at different times of the day in accordance with their location on the then Earth... \n\n\nDov Henis \n(comments from 22nd century)\n
Avatar of: Giuseppe Damiani

Giuseppe Damiani

Posts: 3

January 28, 2011

The coupling between genetic and metabolic oscillators confirms the suggested importance of a simple Yin/Yang mechanism, named metabolic hypercycle (Damiani et al. 1997, Damiani 2007). According to this mechanism, a Lotka-Volterra balance between catabolic-oxidative and anabolic-reductive processes determines cell fate. Transition from anabolic to catabolic phase is regulated mainly by reactive oxygen and nitrose species (ROS and RNS) produced in response to stress or activation signals. The reductive capacity of the major redox couples (GSH/GSSG, NADH/NAD, NADPH/NADP and ATP/ADP) regulates the cytoskeleton and the enzymatic network (based mainly on the Yin/Yang relationships of SIRT1/PARP1and CK2/GSK3) which play a principal role in the cell choice between survival and death pathways. In age-dependent complex disorders the redox balance is disrupted mainly by aggregation of cleaved, glycosylated and misfolded amyloid proteins.\n\nDamiani, G. and P. Della Franca [1997], Morphé and Evolution. Riv. Biol. /B. Forum 90: 227-66.\n\nDamiani, G. [2007], The Yin and Yang of Anti-Darwinian Epigenetics and Darwinian Genetics. Riv. Biol. /B. Forum 100: 361-402. \n
Avatar of: Dov Henis

Dov Henis

Posts: 97

January 29, 2011

EpiDNAtics Is Not Epigenetics\nGenomes Are RNA-Evolved Template Organisms \n\nFrom "Dispel Some Figments Of 2010 Science Imagination"\nhttp://pulse.yahoo.com/_2SF3CJJM5OU6T27OC4MFQSDYEU/blog/articles/245540\n\nThe "heritable or enduring changes" are epiDNAtics, not epigenetics. Alternative splicing is not epigenetics, even if/when not involving alteration of the DNA sequence. Earth life is an RNA world.\n\nIt's the RNAs that evolve proteins. AND IT'S THE RNAs THAT HAVE EVOLVED AND PRODUCE AND EMPLOY THE DNA ( and RNA ) template genome organisms for carrying out life processes, for enhancing Earth's biosphere, for augmenting and constraining as long as possible some energy by augmenting its, RNA's self-propagation, constraining some of the total energy of the universe, all of which is destined to fuel the ongoing cosmic expansion. \n\nIT HAS ALWAYS BEEN AND IT STILL IS AN RNA EARTH LIFE.\n\nScience should adjust its vision, comprehension and concepts. \n\n\nDov Henis \n(comments from 22nd century)
Avatar of: Alexandru Cosciug

Alexandru Cosciug

Posts: 16

January 29, 2011

Please be informed about a news hypothesis sent in August 2008 to First EMBO Conference on Centrosomes and Spindle Pole Bodies, 12-16 September 2008 Heidelberg, Germany.\nAbstract: Brain and soul storming - The necessary and sufficient processes to a well function of the human body are meticulous arranged by specific organizational cells, so called process bio-managers, using interconditioned procedures, transmitted through three ways of communication: chemical or ?protein channel?, electrical or ?ion channel? and mitochondrial or ?EMF wireless channel?. The third type is out of the visible and measurable spectrum and raises a new challenge to the scientists. For this type of bio communication we bring a new theoretical hypothesis, based on the managerial multidisciplinary analysis of a cybernetic model proposed by us, by simulating the human body function with the virtual computerized system based on the management of its total knowledge and its perfect quality way of function. The main bricks used for this virtual construction are: the brain, as main bio-processor, and Eve mtDNA and Adam mtDNA, as bio-antennas. This assembly of the total knowledge, build with ?brain reasoning, biological feeling, and unlimited soul feeling?, is called by us ?main decision triangle, IQ-EQ-CQ?. The main principle of the management of the total knowledge imposes us to not neglect any information produced by man during the time, even if it seems creasy at the beginning. Because in the natural fertilisation the spermatozoids are naturally equipped with the paternal mtDNA (a veritable main bio-GPS), we consider that the paternal mitochondria DNA have a very important role in the evolution of the human being life quality and we have developed a new hypothesis, ?Adam mtDNA theory?, in addition to ?Eve mtDNA theory?.\nKeywords: mitochondria, maternal, paternal\n

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