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

Abstract

AbstractThe molecular clock that generates daily rhythms of behavior and physiology consists of interlocked transcription-translation feedback loops. InDrosophila, 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 ofClocktranscription, 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), aDrosophilahomolog of the TRIP-Br/SERTAD family of transcriptional coregulators, functions with VRI and PDP1 to modulate the circadian period and rhythm strength. Knocking downtarareduces rhythm amplitude and can shorten the period length, while overexpressing TARA lengthens the circadian period. Additionally,taramutants 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 TARA’s role in enhancing VRI and PDP1 activity, overexpressingtarahas a similar effect on the circadian period and rhythm strength as simultaneously overexpressingvriandPdp1. 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. TheDrosophilacircadian 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 theDrosophilamolecular 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.