While scientists have known for several years that our body's internal clock helps regulate many biological processes, researchers have found that the reverse is also true: Many common biological processes – including insulin metabolism – regulate the clock, according to a new study by investigators at the University of Pennsylvania School of Medicine, the Genomics Institute of the Novartis Research Foundation, and the University of California at San Diego.
The new data, published online in Cell this week, suggest that someday physicians may be able to use small molecules that inhibit or stimulate these biological processes in order to influence a person's clock when it gets out of sync due to jetlag or shift work, and to devise new ways to treat metabolic disorders that are intimately tied to the body's daily cycles.
Using a genome-wide screen, the investigators found that reducing expression of any one of hundreds of genes could substantially alter the length of the circadian cycle, which controls the 24-hour sleep/wake cycle. The clock-influencing genes are involved in a large number of biological processes, but the researchers found that components of insulin metabolism, folate metabolism, and the cell cycle were overrepresented in the gene screen, suggesting that these pathways are closely linked to the clock.
"Clock biologists all appreciated that the communication went one direction – from the clock to biological processes – but I don't think anyone anticipated that there would be this level of integration with cell metabolism and the cell cycle, or all these other pathways impinging on clock function," says John Hogenesch, PhD, Associate Professor of Pharmacology in the Institute for Translational Medicine and Therapeutics at Penn. Hogenesch is a co-senior author on the paper with Steve Kay, Dean of the Division of Biological Sciences at UCSD. "There were some hints this might occur for some genes, but not to this extent."
The idea that biological processes might have feedback systems with the circadian clock makes some sense to Hogenesch. For example, he points to the influence of insulin metabolism, saying "If your energy requirements aren't being met, instead of spending a lot of energy on a cell division, a cell might necessarily delay it. It is the same strategy we use when we are not ready to do something, we delay. Maybe procrastination is an evolutionary cellular strategy enabled by the clock to confront situations where resources are limited."
While biologists regularly draw molecular pathways as if they are distinct from one another, they know the reality is much different. "This is a good example showing how dozens of pathways are functionally interconnected with clock function and vice versa," Hogenesch says. "It is important to remember that when you start to change function with a drug, for example, that the perturbation can have unanticipated consequence. Sometimes these consequences are good, but sometimes not."
Hogenesch stresses that while the new experiments show a feedback loop between biological processes and the clock in individual cells in culture, it is not yet clear how feedback systems work in the whole organism. Currently the team is working on biochemical and genetic experiments to answer that question.
In addition to publishing the data in the journal, the investigators have displayed the data on the BioGPS open-access searchable database (http://biogps.gnf.org). The circadian genome-wide screen data can be found at http://biogps.gnf.org/circadian/ and are linked to expression data from Penn, gene function data at Wikipedia and the National Center for Biotechnology Information (NCBI), as well as gene structure information from the University of California at Santa Cruz.
Hogenesch, who helped develop the website when he worked at the Genomics Institute of the Novartis Research Foundation in San Diego, said the site relies on web 2.0 technology and is very simple to use and customize. He and his colleagues built the site because many researchers want to do large database searches but are not computer scientists or informatics specialists. "Andy Su [of Novartis] and I decided to develop a site that even my mom could use, and pitched at the 90% of biologists who want to use something but don't have the skill sets. We decided to build something that would allow them to take advantage of large datasets such as this one."
Co-first authors on the paper are Eric E. Zhang and Tsuyoshi Hirota of the Genomics Institute of the Novartis Research Foundation, and UCSD, and Andrew C. Liu, of the Genomics Institute of the Novartis Research Foundation and the University of Memphis, Tenn. Other authors on the paper include Loren J. Miraglia, Genevieve Welch, Xianzhong Liu, Jon W. Huss III, Jeff Janes, and Andrew I. Su of the Genomics Institute of the Novartis Research Foundation, and Pagkapol Y. Pongsawakul, Ann Atwood, and Steve A. Kay of UCSD.
This research was funded by Silvio O. Conte Center and the National Institute of Mental Health.
PENN Medicine is a $3.6 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is currently ranked #3 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to the National Institutes of Health, received over $366 million in NIH grants (excluding contracts) in the 2008 fiscal year. Supporting 1,700 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System (UPHS) includes its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation's top ten "Honor Roll" hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center, named one of the nation's "100 Top Hospitals" for cardiovascular care by Thomson Reuters. In addition UPHS includes a primary-care provider network; a faculty practice plan; home care, hospice, and nursing home; three multispecialty satellite facilities; as well as the Penn Medicine at Rittenhouse campus, which offers comprehensive inpatient rehabilitation facilities and outpatient services in multiple specialties.
Karen Kreeger | EurekAlert!
Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz
Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
28.04.2017 | Event News
20.04.2017 | Event News
18.04.2017 | Event News
28.04.2017 | Medical Engineering
28.04.2017 | Earth Sciences
28.04.2017 | Life Sciences