TARANIS interacts with VRILLE and PDP1 to modulate the circadian transcriptional feedback mechanism in Drosophila

Abstract

The molecular clock that generates daily rhythms of behavior and physiology consists of interlocked transcription-translation feedback loops. In Drosophila, the primary feedback loop involving the CLOCK-CYCLE transcriptional activators and the PERIOD-TIMELESS transcriptional repressors is interlocked with a secondary loop involving VRILLE (VRI) and PAR DOMAIN PROTEIN 1 (PDP1), a repressor and activator of Clock transcription, respectively. Whereas extensive studies have found numerous transcriptional, translational, and post-translational modulators of the primary loop, relatively little is known about the secondary loop. In this study, using male and female flies as well as cultured cells, we demonstrate that TARANIS (TARA), a Drosophila homolog of the TRIP-Br/SERTAD family of transcriptional coregulators, functions with VRI and PDP1 to modulate the circadian period and rhythm strength. Knocking down tara reduces rhythm amplitude and can shorten the period length, while overexpressing TARA lengthens the circadian period. Additionally, tara mutants exhibit reduced rhythmicity and lower expression of the PDF neuropeptide. We find that TARA can form a physical complex with VRI and PDP1, enhancing their repressor and activator functions, respectively. The conserved SERTA domain of TARA is required to regulate the transcriptional activity of VRI and PDP1, and its deletion leads to reduced locomotor rhythmicity. Consistent with TARAs role in enhancing VRI and PDP1 activity, overexpressing tara has a similar effect on the circadian period and rhythm strength as simultaneously overexpressing vri and Pdp1. Together, our results suggest that TARA modulates circadian behavior by enhancing the transcriptional activity of VRI and PDP1. Statement of SignificanceInternal molecular clocks generating circadian rhythms of around 24 hours broadly impact behavior and physiology, and circadian dysfunction is associated with various neurological and metabolic diseases. The Drosophila circadian clock is a valuable model for understanding the molecular mechanisms underlying daily rhythms as many components of the clock are highly conserved. In this study, we identify a conserved gene, taranis, as a novel regulator of the Drosophila molecular clock. We show that TARANIS modulates circadian behavior by physically interacting with and enhancing the transcriptional activity of clock proteins VRILLE and PDP1. Since mammalian homologs of VRILLE and PDP1 also function in the molecular clock, our results have implications for understanding the mammalian circadian clock.