Two-way Communication Between Common Biological Pathways And Body's Daily Clock

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.