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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM069418-10
Application #
8597880
Study Section
Special Emphasis Panel (ZRG1-CB-W (02))
Program Officer
Sesma, Michael A
Project Start
2004-03-01
Project End
2017-04-30
Budget Start
2013-08-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2013
Total Cost
$287,338
Indirect Cost
$92,338
Name
University of California Davis
Department
Physiology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Harmer, Stacey L; Brooks, Christopher J (2018) Growth-mediated plant movements: hidden in plain sight. Curr Opin Plant Biol 41:89-94
Shalit-Kaneh, Akiva; Kumimoto, Roderick W; Filkov, Vladimir et al. (2018) Multiple feedback loops of the Arabidopsis circadian clock provide rhythmic robustness across environmental conditions. Proc Natl Acad Sci U S A 115:7147-7152
Hughes, Michael E; Abruzzi, Katherine C; Allada, Ravi et al. (2017) Guidelines for Genome-Scale Analysis of Biological Rhythms. J Biol Rhythms 32:380-393
Gray, Jennifer A; Shalit-Kaneh, Akiva; Chu, Dalena Nhu et al. (2017) The REVEILLE Clock Genes Inhibit Growth of Juvenile and Adult Plants by Control of Cell Size. Plant Physiol 173:2308-2322
Müller-Moulé, Patricia; Nozue, Kazunari; Pytlak, Melissa L et al. (2016) YUCCA auxin biosynthetic genes are required for Arabidopsis shade avoidance. PeerJ 4:e2574
Brady, Siobhan M; Burow, Meike; Busch, Wolfgang et al. (2015) Reassess the t Test: Interact with All Your Data via ANOVA. Plant Cell 27:2088-94
Jones, Matthew Alan; Hu, Wei; Litthauer, Suzanne et al. (2015) A Constitutively Active Allele of Phytochrome B Maintains Circadian Robustness in the Absence of Light. Plant Physiol 169:814-25
Hsu, Polly Yingshan; Harmer, Stacey L (2014) Global profiling of the circadian transcriptome using microarrays. Methods Mol Biol 1158:45-56
Hsu, Polly Yingshan; Harmer, Stacey L (2014) Wheels within wheels: the plant circadian system. Trends Plant Sci 19:240-9
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

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