In recent years, Penn researchers have made important strides in identifying molecular components of the clock and learning how they work together to keep a daily rhythm.


Two genes are central to the circadian rhythm, bmal and clock. Without those, the clock ceases to work. But how those genes convey their time to the rest of the body is only partially understood. Mitch Lazar, MD, PhD, director of the Institute for Diabetes, Obesity, and Metabolism at Penn, reported recently that two nuclear receptor genes — Rev-erb alpha and Rev-erb beta — are necessary for maintaining the clock. If one is lost, the other can compensate for its absence. But when both are lost, the clock fails, just like it does when bmal or clock are absent. In other words, the Rev-erb genes are critical gears, not ancillary clock components.

The amount of Rev-erb alpha protein fluctuates on a 24-hour rhythm. When it’s high, it inhibits bmal and clock proteins. Lazar’s team found that the amount of Rev-erb alpha is controlled by an enzyme called GSK3. GSK3 itself is sensitive to lithium, a drug commonly used to control bipolar disorder. The research may explain why lithium helps restore balance in people who suffer from bipolar disorder: The drug may be resetting their internal clock and, with that, their wake and sleep cycles.

The Rev-erb genes though also appear to be lynchpin in the link between the clock and cell metabolism. Previous work showed that heme, best known for its role as the oxygen-carrying component of hemoglobin, also helps regulate sugar metabolism in cells. Lazar’s group found that when there is a lot of Rev-erb in the cell, it binds up heme and slows energy production. As the 24-hour cycle continues and the amount of Rev-erb declines, more heme becomes available to stimulate sugar breakdown, increasing the amount of energy available to the cell.


That up regulation in energy supply correlates with our daily wake-sleep cycle, such that our cells have more energy available when we need to be more active. But that shift can also be a point of danger. Garret A. FitzGerald, MD, director of the Institute for Translational Medicine and Therapeutics at Penn and colleagues found that the circadian shift in metabolism and related hormones drive a rise in blood pressure. That link may partially explain why the risk of heart attacks and strokes is highest early in the day.


Not all of biology runs on a 24-hour cycle though. Some physiological processes fluctuate with the light, following a 12-hour cycle. And recently, John Hogenesch, PhD, associate professor of Pharmacology, and colleagues reported that some processes cycle 3-times a day, or every eight hours. The team sampled RNA every hour for 24-hours from mice livers. They found out that while the most common cycle length was 24-hours (>3,000 genes), both 12-hour (260 genes) and 8-hour (63 genes) were well represented. He says there isn’t an obvious explanation for the 8-hour cycles but speculates that they may have influenced the evolution of our current work-day schedules.

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