Circadian rhythms provide organisms with an adaptive advantage, enhancing the health and fitness of individuals by ensuring that diverse physiological processes occur at the most appropriate times of day. The long-term objective of this proposal is to understand the molecular basis of circadian rhythms in eukaryotic cells. We have identified key regulators of the circadian clock in our previous studies, and will now use genomic, biochemical, genetic, and mathematical modeling approaches to appropriately place these proteins in the circadian system. We will conduct our studies in Arabidopsis thaliana, a model plant that is uniquely well-suited for these experiments due to its compact genome, extensive genetic and genomic resources, and ability to tolerate mutations in chromatin regulatory pathways that are lethal to other complex eukaryotes. We will first use genomic, biochemical, and genetic approaches to characterize the role of a protein conserved across eukaryotes (but of unknown biochemical function) in the regulation of chromatin. We anticipate this work will generate insights into mechanisms governing chromatin organization and thus gene expression in diverse eukaryotes. Next, we will use genetic and biochemical techniques to investigate the roles of a family of related transcription factors in the workings of the circadian oscillator. In the process, we will test predictions made by a mathematical model, evaluating how well this model describes the regulatory relationships that drive the clock. Finally, we will modify an existing competitive chromatin immunoprecipitation protocol to investigate how the binding dynamics of antagonistic transcription factors to chromatin shape the dynamic regulation of gene expression in vivo. These experiments will reveal general principles governing the temporal regulation of gene expression and thus will be applicable to many organisms and processes. Our exploration of shared mechanisms that control circadian clock function in diverse organisms will increase our understanding of how clocks function in humans and shed light on how they promote human health and welfare.

Public Health Relevance

Almost all organisms possess an internal clock that generates roughly 24-hour rhythms in physiology or behavior. Disruption of this circadian clock in humans has serious negative consequences, causing sleep and mood disorders and even contributing to diseases such as cancer. To better understand the molecular basis of circadian rhythms, we are carrying out extensive genetic, biochemical, and genomic studies on the model organism Arabidopsis thaliana.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CB-W (02))
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Sesma, Michael A
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University of California Davis
Schools of Arts and Sciences
United States
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Hsu, Polly Yingshan; Harmer, Stacey L (2014) Wheels within wheels: the plant circadian system. Trends Plant Sci 19:240-9
Hsu, Polly Yingshan; Harmer, Stacey L (2014) Global profiling of the circadian transcriptome using microarrays. Methods Mol Biol 1158:45-56
Anver, Shajahan; Roguev, Assen; Zofall, Martin et al. (2014) Yeast X-chromosome-associated protein 5 (Xap5) functions with H2A.Z to suppress aberrant transcripts. EMBO Rep 15:894-902
Hu, Wei; Franklin, Keara A; Sharrock, Robert A et al. (2013) Unanticipated regulatory roles for Arabidopsis phytochromes revealed by null mutant analysis. Proc Natl Acad Sci U S A 110:1542-7
Jones, Matthew A; Harmer, Stacey (2011) JMJD5 Functions in concert with TOC1 in the arabidopsis circadian system. Plant Signal Behav 6:445-8
Rawat, Reetika; Takahashi, Nozomu; Hsu, Polly Yingshan et al. (2011) REVEILLE8 and PSEUDO-REPONSE REGULATOR5 form a negative feedback loop within the Arabidopsis circadian clock. PLoS Genet 7:e1001350
Ellison, Cory T; Vandenbussche, Filip; Van Der Straeten, Dominique et al. (2011) XAP5 CIRCADIAN TIMEKEEPER regulates ethylene responses in aerial tissues of Arabidopsis. Plant Physiol 155:988-99
Harmer, Stacey (2010) Plant biology in the fourth dimension. Plant Physiol 154:467-70
Rawat, Reetika; Schwartz, Jacob; Jones, Matthew A et al. (2009) REVEILLE1, a Myb-like transcription factor, integrates the circadian clock and auxin pathways. Proc Natl Acad Sci U S A 106:16883-8
Harmer, Stacey L (2009) The circadian system in higher plants. Annu Rev Plant Biol 60:357-77

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