Department of Chemical Engineering, University of California, Santa Barbara, CA 93106.
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
Proc Natl Acad Sci U S A. 2018 Nov 6;115(45):11643-11648. doi: 10.1073/pnas.1803410115. Epub 2018 Oct 22.
The circadian clock orchestrates 24-h rhythms in physiology in most living organisms. At the molecular level, the dogma is that circadian oscillations are based on a negative transcriptional feedback loop. Recent studies found the NAD-dependent histone deacetylase, SIRT1, directly regulates acetylation status of clock components and influences circadian amplitude in cells. While Nakahata et al. [Nakahata Y, Kaluzova M (2008) 134:329-340] reported that loss of increases amplitude through BMAL1 acetylation, Asher et al. [Asher G, Gatfield D (2008) 134:317-328] reported that loss of decreases amplitude through an increase in acetylated PER2. To address this SIRT1 paradox, we developed a circadian enzymatic model. Predictions from this model and experimental validation strongly align with the findings of Asher et al., with PER2 as the primary target of SIRT1. Further, the model suggested SIRT1 influences expression through actions on PGC1α. We validated this finding experimentally. Thus, our computational and experimental approaches suggest SIRT1 positively regulates clock function through actions on PER2 and PGC1α.
生物钟在大多数生物体中协调 24 小时的生理节律。在分子水平上，普遍观点认为生物钟振荡基于负转录反馈环。最近的研究发现，NAD 依赖性组蛋白去乙酰化酶 SIRT1 可直接调节时钟组件的乙酰化状态，并影响细胞中的生物钟振幅。尽管 Nakahata 等人 [Nakahata Y, Kaluzova M (2008) 134:329-340] 报道说缺失会通过 BMAL1 乙酰化增加振幅，但 Asher 等人 [Asher G, Gatfield D (2008) 134:317-328] 报道说缺失会通过增加乙酰化的 PER2 来降低振幅。为了解决这个 SIRT1 悖论，我们开发了一个生物钟酶模型。该模型的预测和实验验证与 Asher 等人的研究结果非常吻合，PER2 是 SIRT1 的主要靶标。此外，该模型表明 SIRT1 通过对 PGC1α 的作用影响 的表达。我们通过实验验证了这一发现。因此，我们的计算和实验方法表明，SIRT1 通过对 PER2 和 PGC1α 的作用来正向调节生物钟功能。
