The circadian clock plays a vital role in the health and fitness of organisms by regulating cellular activities to specific times of the day and night. The long-term goal of this proposal is to understand how circadian clocks function within eukaryotic cells. Forward genetic approaches have been instrumental to initially identify many molecular components of the circadian clock in plants and animals revealing a shared molecular architecture. Recent progress in the circadian field has been focused on the characterization of the precise molecular wiring that builds the clock circuitry which ultimately will uncover how the circadian clocks control daily rhythms in physiology, metabolism and behavior in different species. By developing a complete transcription factor (TF) collection for the model organism Arabidopsis thaliana we have recently implemented a reverse genomic strategy that allowed us refine the transcriptional circuits that build the circadian clock in plants. Based on our initial discoveries we will continue using our TF collection to determine direct regulators of clock genes and implement the discovery of new transcriptional mechanisms by TF-focused gain-of-function screens. In addition, we propose computational approaches to build a map that connects identified clock components with clock-output genes and the genome-wide identification of mechanisms for the non-transcriptional circadian regulation of mRNA and protein levels. In sum, we propose a suite of genomic approaches to expand our transcriptional discovery program and extend our discovery pipeline to the post-transcriptional and post-translational levels. Given the ubiquity and relevance of the circadian clock, the identification of common clock mechanisms will help us understand how alterations in the circadian pacemaker have such a tremendous impact on human well- being.
Almost all organisms possess circadian clocks that control daily rhythms in physiology, metabolism and behavior. The molecular architecture of these clocks appears similar amongst all organisms. Thus the advances learned in model systems such as Arabidopsis will be broadly applicable to understanding rhythms in humans and the known pathologies associated with their dysfunction in a wide range of diseases to impact the treatment of human circadian disorders such as diabetes, SAD, insomnia and jet- lag.
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