Penn researchers unwind the mysteries of the cellular clock

PHILADELPHIA - Human existence is basically circadian. Most of us wake in the morning, sleep in the evening, and eat in between. Body temperature, metabolism, and hormone levels all fluctuate throughout the day, and it is increasingly clear that disruption of those cycles can lead to metabolic disease. Underlying these circadian rhythms is a molecular clock built of DNA-binding proteins called transcription factors. These proteins control the oscillation of circadian genes, serving as the wheels and springs of the clock itself. Yet not all circadian cycles peak at the same time - some peak in the morning and others in the evening. The question, is, how does a single clock keep time in multiple phases at once? Now, thanks to new findings from researchers at the Perelman School of Medicine at the University of Pennsylvania, we know. In the current issue of the journal Cell, Mitchell Lazar, MD PhD, the Sylvan Eisman Professor of Medicine and director of the Institute for Diabetes, Obesity, and Metabolism and his team report the results of a genome-wide survey of circadian genes and genetic regulatory elements called enhancers. These are key parts of the "dark matter" of the genome; rather than encoding proteins, they control the expression of genes. Led by postdoctoral researchers Bin Fang, Logan Everett and Jennifer Jager, Lazar's team took advantage of new tools based on high-density DNA sequencing to measure the activity of enhancers throughout the day in the livers of mice. They found that many enhancers, like circadian genes themselves, have a daily oscillation that is in phase with nearby genes - both the enhancer and gene activity peak at the same time each day. The enhancer activities, in turn, are governed by distinct proteins called transcription factors. Grouping the enhancers into eight three-hour phases based on when they peak, the group asked which factors are capable of binding to the enhancers in each set. Remarkably, the team found that enhancers that are in the same phase tend to bind the same transcription factors. For instance, a well-known circadian component called CLOCK binds enhancers that are most active during one particular three-hour period. Another protein called Rev-erb binds 12 hours later. Loss of any one of those factors dysregulates a subset of oscillating genes while leaving genes tuned to other circadian phases unaffected. "Different transcription factors control different phases," Lazar concludes. "That explains how one clock leads to at least eight different subclocks."

Importantly, genes that oscillate with the same phase tend to have related functions, which are distinct from the metabolic pathways controlled at other times. Genes involved in insulin signaling peak at a different time than genes that control sugar metabolism, for instance. Lazar suggests it might be possible to tweak pharmaceutical regimens to make them more efficient, by delivering drugs only when the pathways they impact are actually active - a strategy that could minimize unintended side effects, he says. "As a proof of concept for a new principle of drug treatment for metabolic disorders," he says, "this is a real step in that direction."

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Other Penn authors on the study include Erika Briggs, Sean Armour, Dan Feng, Ankur Roy, Zachary Gerhart-Hines, and Zheng Sun. The study was funded by the National Institutes of Health (R01 DK45586, F32 DK095526, K99 DK099443, F32 DK095563) and the JPB Foundation. Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2013 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; Chester County Hospital; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2013, Penn Medicine provided $814 million to benefit our community.