Abstract
In the negative feedback loop comprising the Neurospora circadian oscillator, the White Collar Complex (WCC) formed from White Collar-1 (WC-1) and White Collar-2 (WC-2) drives transcription of the circadian pacemaker gene frequency (frq). Although FRQ-dependent repression of WCC has been extensively studied, the mechanism by which the WCC initiates a circadian cycle remains elusive. Structure/function analysis of WC-1 eliminated domains previously thought to transactivate frq expression but instead identified amino acids 100–200 as essential for frq circadian expression. A proteomics-based search for coactivators with WCC uncovered the SWI/SNF (SWItch/Sucrose NonFermentable) complex: SWI/SNF interacts with WCC in vivo and in vitro, binds to the Clock box in the frq promoter, and is required both for circadian remodeling of nucleosomes at frq and for rhythmic frq expression; interestingly, SWI/SNF is not required for light-induced frq expression. These data suggest a model in which WC-1 recruits SWI/SNF to remodel and loop chromatin at frq, thereby activating frq expression to initiate the circadian cycle.
Highlights
Circadian clocks are key cellular mechanisms regulating a wide variety of physiological and molecular activities
The White Collar Complex (WCC), a heterodimer comprised of White Collar-1 (WC-1) and White Collar-2 (WC-2), serves as the transcriptional activator for the pacemaker gene frequency by binding to one of two DNA elements, the Clock box (C box) [1] in the dark or the Proximal Light-Response Element (PLRE) in the light [2]
Circadian clocks govern behavior in a wide variety of organisms. These clocks are assembled in such a way that proteins encoded by a few dedicated ‘‘clock genes’’ form a complex that acts to reduce their own expression
Summary
Circadian clocks are key cellular mechanisms regulating a wide variety of physiological and molecular activities. Neurospora has been for several decades an excellent model for studies of the eukaryotic circadian clock characteristic of fungi and animals. In this organism, the White Collar Complex (WCC), a heterodimer comprised of WC-1 and WC-2, serves as the transcriptional activator for the pacemaker gene frequency (frq) by binding to one of two DNA elements, the Clock box (C box) [1] in the dark or the Proximal Light-Response Element (PLRE) in the light [2]. FRQmediated WCC repression has been extensively studied, whereas how WC-1 as a transcription factor drives frq expression in a circadian cycle is still poorly understood. No experimental data have yet confirmed their in vivo functions
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