Department of Neuroscience, the Farber Institute for Neurosciences, and Synaptic Biology Center, Thomas Jefferson University, Philadelphia 19107, Pennsylvania.
Department of Neuroscience, the Farber Institute for Neurosciences, and Synaptic Biology Center, Thomas Jefferson University, Philadelphia 19107, Pennsylvania
J Neurosci. 2024 Jan 31;44(5):e0922232023. doi: 10.1523/JNEUROSCI.0922-23.2023.
The molecular clock that generates daily rhythms of behavior and physiology consists of interlocked transcription-translation feedback loops. In , 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 transcription, respectively. Whereas extensive studies have found numerous transcriptional, translational, and posttranslational 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 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 reduces rhythm amplitude and can shorten the period length, while overexpressing TARA lengthens the circadian period. Additionally, 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 TARA's role in enhancing VRI and PDP1 activity, overexpressing has a similar effect on the circadian period and rhythm strength as simultaneously overexpressing and Together, our results suggest that TARA modulates circadian behavior by enhancing the transcriptional activity of VRI and PDP1.
产生行为和生理日常节律的分子钟由相互连锁的转录-翻译反馈环组成。在这篇文章中，涉及 CLOCK-CYCLE 转录激活因子和 PERIOD-TIMELESS 转录阻遏物的主要反馈环与涉及 VRILLE（VRI）和 PAR 结构域蛋白 1（PDP1）的次要环相互连锁，分别是转录的阻遏物和激活物。尽管广泛的研究发现了许多主要环的转录、翻译和翻译后调节剂，但对次要环相对知之甚少。在这项研究中，我们使用雄性和雌性果蝇以及培养细胞证明了 TARANIS（TARA），一种 TRIP-Br/SERTAD 家族转录共调节剂的同源物，与 VRI 和 PDP1 一起调节生物钟周期和节律强度。敲低 会降低节律幅度并缩短周期长度，而过表达 TARA 则会延长生物钟周期。此外， 突变体表现出较低的节律性和 PDF 神经肽的表达降低。我们发现 TARA 可以与 VRI 和 PDP1 形成物理复合物，分别增强它们的阻遏物和激活物功能。TARA 的保守 SERTA 结构域是调节 VRI 和 PDP1 转录活性所必需的，其缺失会导致运动节律性降低。与 TARA 增强 VRI 和 PDP1 活性的作用一致，过表达 对生物钟周期和节律强度的影响与同时过表达 和 相似。总之，我们的结果表明，TARA 通过增强 VRI 和 PDP1 的转录活性来调节生物钟行为。
