Apr. 22, 2002 BOSTON, MA –- 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 Harvard Medical School and the Harvard School of Public Health report in the April 21 Nature online. The study, among the first to explore circadian time mechanisms outside the brain, could have a potentially broad impact on the burgeoning fields of circadian medicine and postgenomic science.
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, and that is that the relationship between gene regulation and physiology has a giant black box," said the study’s principal investigator, Charles Weitz, Assistant Professor of Neurobiology at Harvard Medical School.
The existence of peripheral timepieces had been suspected but no one knew how much control they actually had or why they were in organs such as the heart, lungs, and liver in the first place. Using newly developed gene chips, Charles Weitz, Kai-Florian Storch, Research Fellow in Neurobiology at Harvard Medical School and lead author of the study, and colleagues monitored the activity of 12,000 genes—one third the entire mouse genome—in the hearts and livers of mice at various points during the day. Mathematical models developed by Wing Wong, Professor of Computational Biology at Harvard School of Public Health, revealed that eight to ten percent were expressed in a markedly circadian rhythm in both the heart and liver. "That is a pretty big chunk of the genome," said Weitz.
At 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 master clock, the 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 mid-morning—a finding that Weitz cannot yet explain.
However, further analysis revealed a remarkable similarity. Using a program that analyzes individual gene’s functions, 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. The answer to the question, ‘why are there peripheral clocks?’ seems to be that they are performing these essential functions, though by very different proteins.
It is not clear how or why the heart and liver uses different genes to carry out similar tasks. "There is no simple way to tie the bow," said Weitz. "But it potentially opens the door to a kind of complexity that we now have to think about."
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