Transcriptional Regulation via Nuclear Receptor Crosstalk Required for the Drosophila Circadian Clock

May 26, 2015Current biology : CB

Gene control through interactions between nuclear receptors needed for the fruit fly's daily biological clock

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Abstract

The nuclear receptor E75 is a key component of the Drosophila molecular clock.

E75 and UNF bind to regulatory sequences of the period (per) gene.
These nuclear receptors enhance the transcription of the per gene mediated by CLK/CYC.
Their action completes the core transcriptional feedback loop necessary for circadian rhythms in Drosophila.
This study suggests that transcriptional regulation via nuclear receptors is significant in metazoan circadian clocks.

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Circadian clocks in large part rely on transcriptional feedback loops. At the core of the clock machinery, the transcriptional activators CLOCK/BMAL1 (in mammals) and CLOCK/CYCLE (CLK/CYC) (in Drosophila) drive the expression of the period (per) family genes. The PER-containing complexes inhibit the activity of CLOCK/BMAL1 or CLK/CYC, thereby forming a negative feedback loop [1]. In mammals, the ROR and REV-ERB family nuclear receptors add positive and negative transcriptional regulation to this core negative feedback loop to ensure the generation of robust circadian molecular oscillation [2]. Despite the overall similarities between mammalian and Drosophila clocks, whether comparable mechanisms via nuclear receptors are required for the Drosophila clock remains unknown. We show here that the nuclear receptor E75, the fly homolog of REV-ERB α and REV-ERB β, and the NR2E3 subfamily nuclear receptor UNF are components of the molecular clocks in the Drosophila pacemaker neurons. In vivo assays in conjunction with the in vitro experiments demonstrate that E75 and UNF bind to per regulatory sequences and act together to enhance the CLK/CYC-mediated transcription of the per gene, thereby completing the core transcriptional feedback loop necessary for the free-running clockwork. Our results identify a missing link in the Drosophila clock and highlight the significance of the transcriptional regulation via nuclear receptors in metazoan circadian clocks.

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Transcriptional Regulation via Nuclear Receptor Crosstalk Required for the Drosophila Circadian Clock

Abstract

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