Outline

Hibernation

Circadian Clock

Research Subjects at a glance

Circadian Rhythm
Circadian rhythm is universally present from unicellular organisms to complex organisms, and plays an important role in physiological processes such as the sleep-wake cycle in mammals. By integrating all available microarray experiments on circadian rhythm in different tissues and species in mammals, we identified a set of common circadian genes lying in the center of the circadian clock (Yan et al. 2008b). Significant differences in the circadian oscillation of gene expression among mouse, rat, macaque, and human have been observed that underlie their physiological and behavioral differences. We constructed a gene regulatory network for the mouse circadian rhythm using knockout or mutant microarray data that have previously received little attention. Further analysis revealed not only additional feedback loops in the network contributing to the robustness of circadian clock, but also how environmental factors such as light, food, and heat can entrain the circadian rhythm. Our study provides the first gene regulatory network of the mammalian circadian rhythm at the system level. It is also the first attempt to compare gene regulatory networks of circadian rhythm in different mammalian species.

Medium and Long Term Research Goals
After being part of the department of computational genomics in PICB between September 2006 and March 2009, Functional Genomics group became a Young Independent Research Group in PICB in March 2009. We will continue to use systems biology and computational biology approaches to study the molecular mechanisms of complex physiological processes: hibernation, circadian rhythm, and sleep. Especially, we will focus on the following close-related research directions: Bear hibernation Most hibernation genomic studies have focused on the small-sized hibernators such as ground squirrel species. However, hibernation is a wide spread phenomenon shared in diverse families among at least six orders of mammals. Bear is a unique model organism to study hibernation in human-sized hibernators. Unveiling the molecular mechanisms in bear hibernation will help to identify not only the universal features of mammalian hibernation but also the bear-specific hibernation responses. However, the genomic study of bear hibernation has been hampered by the scarcity of bear genomic resources. Collaborating with Dr. Vadim B Fedorov, we conducted sequencing and in-depth analysis of 38,757 Expressed Sequence Tag Sequences (ESTs) of American black bear (Ursus americanus). Such genomic resource will be used as the basis to develop cDNA arrays for gene expression profiling of bears during hibernation.

Induced hibernation-like states
The induction of hibernation-like state in non-hibernators such as human has enormous medical applications. In 2005, Roth et al. have reported the induction of suspended animation-like state by hydrogen sulfide in mice. In fact, many sedative drugs in general anesthesia have body temperature lowering effect. Although anesthesia has been used routinely in clinics, the neuronal and molecular mechanism how it exerts its inhibitory effect on the nerve system is largely unknown. We are collaborating with Dr. Yousheng Shu and Dr. Yuqiang Ding in Institute of Neuroscience to study the gene expression changes in mice during the entry into and arousal from anesthesia. Electrical activities of the brain and behavioral properties will be measured to characterize the brain states of mice in anesthesia. Such studies will help us understand how the suspension of animation is achieved and reversed. Especially, it will pave the way for designing new drugs for deeper suspension of animation, i.e. hibernation-like state, in human.

Sleep
As a naturally occurring state of suspension of animation, sleep phenotype has been observed in a wide range of animals. Sleep has been under the control of circadian rhythm and homeostatic regulation. We will apply a similar computational approach that we have used for mammalian circadian rhythm to construct a gene regulatory network for sleep in mammals. So far, we have collected microarray data of sleep deprivation in mouse, rat, sparrow, and fruit fly. Comparing the results across different species, we will identify the species-specific and conserved aspects of molecular responses to sleep deprivation. We are also collaborating with Dr. Jiuling Du in Institute of Neuroscience to study the circadian rhythm and sleep in zebrafish. Zebrafish has emerged as a model organism to study animal behavior recently. We have established a behavioral platform to monitor zebrafish activity. Circadian rhythm and sleep states in zebrafish have been established in our pilot study. We will measure the gene expression changes during circadian rhythm and sleep in zebrafish using microarray and conduct comparative studies with the results in other species.

List of Publications

• Wang, H., et al., Computational analysis of gene regulation in animal sleep deprivation. Physiol Genomics, 2010. 42(3): p. 427-36.here
• Liu, Y., et al., Genomic analysis of miRNAs in an extreme mammalian hibernator, the Arctic ground squirrel. Physiol Genomics, 2010. 42A(1): p. 39-51.here
• Shao, C., et al., Shotgun proteomics analysis of hibernating arctic ground squirrels. Mol Cell Proteomics, 2010. 9(2): p. 313-26.[pdf]
• Zhao, S., et al., Genomic analysis of expressed sequence tags in American black bear Ursus americanus. BMC Genomics, 2010. 11: p. 201.[pdf]
• Yan, J., et al., Modulation of gene expression in hibernating arctic ground squirrels. Physiol Genomics, 2008. 32(2): p. 170-81.[pdf]
• Yan, J., et al., Analysis of gene regulatory networks in the mammalian circadian rhythm. PLoS Comput Biol, 2008. 4(10): p. e1000193. [pdf]
• Yan, J., et al., Detection of differential gene expression in brown adipose tissue of hibernating arctic ground squirrels with mouse microarrays. Physiol Genomics, 2006. 25(2): p. 346-53.[pdf]
• Yan, J. and T.G. Marr, Computational analysis of 3'-ends of ESTs shows four classes of alternative polyadenylation in human, mouse, and rat. Genome Res, 2005. 15(3): p. 369-75.[pdf]