Molecular Control of Circadian Rhythm in Animals


     The circadian clock is an intrinsic time-keeping mechanism that controls daily rhythms of numerous physiological processes, such as sleep/wake behavior, body temperature, hormone secretion, and metabolism. The temporal coordination allows anticipation of daily environmental changes, and therefore provides fitness advantage to organisms. Because of the tight connection between the clock and physiology, perturbations to clock function by genetic mutations or environmental factors (for example, shift work and jet lag) have been implicated in sleep disorders, cancer, cardiovascular and metabolic diseases. Therefore, understanding the circadian clock system has strong impact on human health.

     Circadian rhythms are generated in a cell-autonomous manner through transcriptional regulatory networks of the clock genes. Although more than a dozen of clock genes have been discovered, we still do not know how the network generates precise ~24 hour rhythms, how the clock controls physiological outputs, and so on. Also, how can we translate findings on the molecular clock to improve human health? This is one of the biggest challenges in the circadian field. To address these fundamental questions, our group has established new approaches to search for modifiers of clock function through cell-based high-throughput screening. From a genome-wide RNAi screen in human cells, we identified more than 200 clock modifier genes that cause robust period change or high amplitude upon knockdown. We further applied chemical biology approaches that utilize chemicals to perturb and dissect biological mechanisms. From the screening of hundreds of thousands of chemical compounds with diverse structures, we isolated a number of small molecules that dramatically change the circadian period. We employed an affinity-based proteomic approach to identify molecular targets of the compounds, resulting in the discovery of new inhibitors of casein kinase I and a first-in-class small molecule targeting the core clock protein CRY. Functional characterization of these compounds revealed important features of the clock machinery. We are also interested in the regulation of metabolism by the circadian clock. One of the major functions of the liver is glucose production in response to fasting hormones such as glucagon to maintain glucose homeostasis. Our group has discovered that this process shows circadian rhythms in vivo and is controlled by the core clock protein CRY.

     By using the resources of clock modifying compounds and genes in combination with state-of-the-art technologies at ITbM, the Kay-Hirota group aims to discover "transformative bio-molecules" that will revolutionize clock research and ultimately benefit human health. A unique combination of molecular, genetic, genomic, biochemical, and chemical biology approaches will allow us to reveal key regulatory processes of the circadian clock and define molecular links between the clock and rhythmic regulation of physiology and behavior. Proof-of-concept chemical probes will provide useful tools to control clock function in a conditional manner and also act as starting points for developing therapeutics for circadian clock-related disorders.