Scripps Research Scientists Identify New Mechanism Regulating Daily Biological Rhythms
(What goes around, comes around, and, in fact, its cycles are regulated…)
In a study published November 12 in the Journal of Biological Chemistry, scientists from the Jupiter campus of The Scripps Research Institute announced that they have identified a mechanism that regulates circadian rhythm, the master clock that controls the body’s natural 24-hour cycle. These new findings may help scientists in their search for treatments for sleep disorders, diabetes, obesity as well as some types of cancer.
“It’s well known that the “nuclear receptors” RORα and REV-ERBα, regulate expression of the gene, BMAL1, which is vital to virtually every aspect of human physiology and a core component of the circadian clock,” said Tom Burris, a professor in the Department of Molecular Therapeutics at Scripps Florida who led the study. But, he added, scientists did not how…
By way of explanation, nuclear receptors are proteins that recognize and regulate genes. They have “ports,” so to speak, that scientists can either block or send a protein to bind with, for a desired effect. As a result, the receptors control an organism’s metabolism by activating gene expression.
Gene expression is the scientific term used to describe the process where the information contained in DNA is transcribed into Messenger DNA (MRNA), and then is translated into the proteins necessary to perform critical cell functions. (DNA copies itself backwards into RNA. That process is called transcription. If a gene is not transcribed, it just sits in the cell inactive).
Now, back to the study. Here’s what the Scripps study found: The variations of the distribution of the proteins RORα and REV-ERBα not only regulate the activation of BMAL1, but also of the protein, NPAS2.
And, the scientists asked, since the expression of RORα and REV-ERBα follows a 24-hour circadian pattern, with opposing phases, and leads to the correct circadian pattern of gene expression of BMAL1 and NPAS2, what is the mechanism that governs that?
“We think it’s something of a competition between these two receptors for binding to promoters (proteins that allow expression) of these genes that triggers either the activation (RORα) or repression (REV-ERBα) of the gene,” Burris said.
Learning more about this process is important, because disorders linked to dysfunctional circadian rhythms can be severe and potentially deadly.
“When you’re dealing with circadian rhythm, the most obvious disease target is sleep – for people who do shift work, critical jobs like police work, fire fighting, and medicine,” he said. “If circadian rhythm is disrupted, you’re prone to metabolic disorders like diabetes and obesity and even breast cancer – because the core clock is closely linked to the cell cycle. If your clock goes awry, you run the risk of your cell cycle going awry as well.”
Nuclear receptors have been implicated in a number of cancers, including prostate, breast, and colon cancers, and other diseases as well, including type 2 diabetes, atherosclerosis, and metabolic syndrome.
In addition, nuclear-receptor proteins can be influenced by specific drugs, and so they can be activated by compounds such as the sex hormones, vitamins A and D, and glucocorticoids, which modulate the body’s response to stress. Actually, Scripps scientists have already identified several new drug-like molecules that can influence both of these receptor proteins.
As more is understood about the relationship between these receptors and their gene targets, researchers can consider the possibility of modulating the body’s core clock.
The first author of the study, “Characterization of the Core Mammalian Clock Component, NPAS2, as a REV-ERBα/RORα Target Gene,” is Christine Crumbley of The Scripps Research Institute. Others authors include Yongjun Wang and Douglas J. Kojetin, also of Scripps Research. For more information, see http://www.jbc.org/content/285/46/35386.abstract
This work was funded by the National Institutes of Health.
The Scripps Research Institute, a large independent, non-profit biomedical research organization, is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular and infectious diseases, and synthetic vaccine development.
Headquartered in La Jolla, California, the institute also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Scripps Florida is located in Jupiter.