Gene Scan Shows Body's Clock Influences Numerous Physical Functions

The pineal gland -- integral to setting the body's sleep and wake cycles -- may be involved in a broad range of bodily functions, according to a study by researchers at the National Institutes of Health and other institutions.

Using a technology that scans for the activity of thousands of genes at a time, the researchers found that the activity of more than 600 genes in the pineal gland are synchronized in some way with the 24-hour sleep and wake cycle. The genes influence such diverse functions as inflammation and immunity.

Researchers have traditionally studied the gland in hopes of gaining insight into the health problems of shift workers and people who frequently travel between time zones. The pineal gland produces the hormone melatonin, which regulates the cycle of sleep and waking.

"The results of this study indicate that the pineal gland may be involved in a far greater range of physiological functions than we thought," said Duane Alexander, M.D., director of NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development, where much of the research took place. "An understanding of how the pineal gland interacts with the genes that the researchers identified could provide insight into a broad range of disorders and conditions."

The study appears in the March 20, 2009 issue of The Journal of Biological Chemistry. The study's first author was Michael J. Bailey, of the NICHD Section on Neuroendocrinology. Other authors of the paper were from the NIH Center for Information Technology, NIH's National Institute of Mental Health, Cardiff University, Wales, the University of Copenhagen, Denmark, King's College of London, England, and The Genomics Institute of the Novartis Research Foundation, San Diego, Calif.

The pineal gland is located within the brain, explained the study's senior author, David Klein, Ph.D., Chief of the Section on Neuroendocrinology. To conduct the study, Dr. Klein and his colleagues analyzed rodent pineal glands with a gene chip, a device that can analyze the activity of thousands of genes at a time. The researchers found that the activity of 604 genes changed on a 24-hour schedule, more than has been reported to occur in any other tissue.

The researchers discovered that these genes increase their activity from 2- to 100-fold during a 24-hour cycle. About 70 percent of the genes were found to increase activity at night, the remaining 30 percent during the day. The genes are involved in a variety of functions, and govern such processes as:

• inflammation (swelling)
• the immune response
• cell adhesion (how cells bind, or join together)
• the cell cycle (the reproduction and death of cells)
• the cytoskeleton (the inner structural material of cells)
• calcium metabolism
• cholesterol production
• endothelial tissue (the tissue that lines many of the -- body's organs and structures)
• transcription (the process by which DNA sequences are -- eventually converted through RNA into proteins)
• effects of the thyroid gland on the pineal gland
• cell signaling (the process through which hormones and -- other factors control cells)
• copper and zinc biology

"We were really surprised by what we found," Dr. Klein said. "We did not expect to find 24-hour rhythms in the functioning of so many genes."

Dr. Klein said that, as he and his coworkers expected, many of the genes active in the pineal gland are also active in the retina of the eye. The study authors cited this finding as highly compelling evidence that the pineal gland and the retina evolved from the same primitive light detecting structure. An earlier study on this possible evolutionary relationship is available at: http://www.nichd.nih.gov/news/releases/Pages/pinealgland.aspx.

The pineal gland is controlled by a brain structure known as the suprachiasmic nucleus, located at the base of the brain, Dr. Klein said. The suprachiasmatic nucleus is known as The Mind's Clock, because it coordinates body rhythms in response to changes in lighting that are detected by the eyes. The suprachiasmatic nucleus is connected to the pineal gland by nerve cells. At night, a brain chemical called norepinephrine, which transmits information through nerve cell networks, is released in the pineal gland. Norepinephrine, in turn, stimulates the production of another compound within the cells of the pineal gland, known as cyclic adenosine monophosphate (cyclic AMP). Cyclic AMP causes the pineal gland to produce melatonin.

The researchers noted that the daily changes in gene activity observed in the study were controlled by the release of norepinephrine and the increase of cyclic AMP.

"This is surprising, because we did not anticipate that the release of one molecule -- norepinephrine -- would be found to control the activity of hundreds of genes," Dr. Klein said. "It appears that this one signal triggers a highly complex response that is necessary for normal rhythmic function of the pineal gland."

Dr. Klein added that he and his colleagues are planning future studies to discern both how the cells of the pineal gland are controlled and how they influence the genes controlling other cellular functions.

"We have a long way to go before we can fully understand the role of the pineal gland and what makes it tick," Dr. Klein said. "I suspect that the pineal gland plays a much broader role in human health than anyone has ever imagined."

This research was funded by the Intramural Research Program of the NICHD; the Center for Information Technology; The Wellcome Trust; the Biological Sciences Research Council; the Lundbeck Foundation; the Danish Medical Research Council; the Novo Nordisk Foundation; the Carlsberg Foundation; the Fonden til Lægevidenskabens Fremme; the Simon Fougner Hartmanns Familiefond; and Pennsylvania Commonwealth Health Research Formula Funds.

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The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Institute’s Web site at http://www.nichd.nih.gov/.

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