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NEUROBIOLOGYPeripheral 'Swatch' Watches Are Powerful Force in Modulating Body's Circadian RhythmsDiscovery that Clocks in Organs Use Different Genes Could Affect Circadian Medicine The daily rhythms of the body--once thought to be strictly governed by a master clock lodged in the brain--appear to be driven to a remarkable degree by tiny timepieces pocketed in organs all over the body. What's more, these peripheral timepieces appear to be strikingly idiosyncratic in appearance--more like Swatch watches than classic Timexes. Clocks located in the liver and heart appear to use very different sets of genes to perform essentially the same functions, researchers at HMS and HSPH report in the April 21 Nature online. The study, among the first to explore timing mechanisms outside the brain, could have a broad impact on the burgeoning fields of circadian medicine and postgenomic science.
The discovery of independent timing mechanisms in heart and liver "suggests a type of flexibility to organ function that no one ever imagined," said Charles Weitz (front right). Weitz's colleagues are (clockwise from front left) Wing Wong, Kai-Florian Storch, Ovidiu Lipan, and Igor Leykin. (Photo by Steve Gilbert) Clinicians have known for years that organs function at different rates--the heart beats, kidneys transport ions and electrolytes, the liver metabolizes lipids, sugars, and amino acids differently over the course of the day--and have used this knowledge to design more effective drug regimens for patients. A better understanding of what drives those local rhythms, and how they go wrong, could aid physicians' efforts. The discovery that different genes perform similar circadian functions also bears on attempts to move beyond the Human Genome Project, to find functions for the tens of thousands of newly described genes. "There is a lesson here beyond clocks--the relationship between gene regulation and physiology has a giant black box," said Charles Weitz, HMS associate professor of neurobiology and senior author on the study. Kai-Florian Storch, HMS research fellow in neurobiology, is lead author. Big Ben and BeyondThe evidence for the existence of peripheral timepieces has been accumulating for the past few years. To begin, proteins expressed in the brain's master clock, located in the suprachiasmatic nucleus, were discovered in organs such as the heart and liver--and they were expressed in the same rhythmic fashion as in the suprachiasmatic nucleus. More recently, experiments showed that under conditions of stress, these rhythmic expression patterns in organs could be altered independently of the master clock--suggesting that the peripheral clocks were to some extent autonomous. "So the peripheral clocks are not just slaves," said Weitz. Still, no one knew how much control over daily functions these peripheral clocks actually had or what exactly they were doing in organs like the heart, lungs, and liver in the first place. Were they driving a core set of functions that all organs need to perform, or were they each doing their own thing in their different locations? Using newly developed gene chips, Weitz, Storch, and colleagues monitored the activity of 12,000 genes--one third of the entire mouse genome--in the hearts and livers of mice at various points during the day. Using mathematical models developed by Ovidiu Lipan, a postdoc in the laboratory of Wing Wong, HSPH professor of computational biology and professor of statistics in the Harvard University Faculty of Arts and Sciences, they were able to tease out those genes that were expressed in a markedly circadian rhythm in the liver and heart, which amounted to eight to 10 percent for each organ. Timing Is EverythingAt first sight, the gene sets retrieved from the liver and heart displayed enormous differences. Of the more than 460 heart and nearly 600 liver genes, the researchers found only 37 circadian genes in common. Many were genes originally discovered in the brain's suprachiasmatic nucleus and are probably core clock components. The remaining genes, whose expression is presumably under the clock's control, exhibited markedly different expression patterns. Peak expression for liver genes occurred at various points throughout the day while nearly all the heart genes exhibited greatest output at the same time, about midmorning--a finding that Weitz cannot yet explain. However, further analysis revealed a remarkable similarity. Using a program that analyzes the function of individual genes, Gene Ontology, the researchers learned that though different in composition, the gene sets were performing remarkably similar tasks in cells, from communication to transport, metabolism, and cell death. So why are there peripheral clocks? The answer seems to be that they are performing these essential functions, though with very different proteins. It is not clear how or why the heart and liver use different genes to carry out similar tasks. "There is no simple way to tie the bow," said Weitz. "But it may open the door to a kind of complexity we now have to think about." --Misia Landau |
