Circadian Programs in Bacteria

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION (provided by applicant): Organisms from bacteria to humans manifest circadian (daily) rhythms that are controlled by an endogenous biochemical oscillator. Many processes, including sleeping/waking, body temperature, homeostatic functions, gene expression, cell division, and enzymatic activities, are regulated by these "biological clocks" and are important to human physiology. Psychiatric and medical studies have shown that circadian rhythmicity is involved in some forms of depressive illness, "jet lag," drug tolerance/efficacy, sleep disorders, and other aspects of human physiology. Therefore, understanding the molecular basis of circadian clocks is of fundamental biological interest and may lead to insights that will be useful in the diagnosis and treatment of disorders that are relevant to sleep, mental health, and pharmacology. Although recent breakthroughs in the field of circadian rhythms have identified a number of proteins that appear to act as clock components, we have only just begun to understand how these components interact functionally with themselves to generate precise, temperature-compensated, entrainable 24 hour oscillations. Although the specific clock proteins in cyanobacteria, Neurospora, Drosophila, and mammals are different, evidence from these diverse organisms supports a common model that proposes autoregulatory feedback loops of central clock gone expression; these observations encourage a comparative approach. This project focuses on the least-complex and most technically malleable organism in which a biological clock has been demonstrated, namely the cyanobacterium, Synechococcus elongatus 7942. The advantages that accrue from using this organism are its small genome, diverse genetic tools, and luciferase reporters. In this organism the monitoring of circadian gene expression is the most facile of any system presently available. Therefore, this cyanobacterial system has excellent tools for detailed molecular/genetic analyses and for clock investigations. The project will use this bacterium to address two major aspects of biological rhythmicity. First, hypotheses about its fundamental mechanism will be tested by studying the structure, function, and expression patterns of the key clock protein, KaiC. A new temperature conditional mutant will be characterized. A hypothesis that changes in chromosomal structure mediate global circadian regulation of gene expression will be tested. Second, the fitness advantage conferred by circadian control of metabolism will be characterized, including studying its mechanism.