Tanoue Shintaro, Fujimoto Katsumi, Myung Jihwan, Hatanaka Fumiyuki, Kato Yukio, Takumi Toru
Graduate School of Biomedical Sciences, Hiroshima University , Hiroshima , Japan.
Graduate School of Biomedical Sciences, Hiroshima University , Hiroshima , Japan ; RIKEN Brain Science Institute , Wako, Saitama , Japan.
Front Neurol. 2015 Jul 23;6:166. doi: 10.3389/fneur.2015.00166. eCollection 2015.
The circadian oscillation of clock gene expression in mammals is based on the interconnected transcriptional/translational feedback loops of Period (Per) and Bmal1. The Per feedback loop initiates transcription through direct binding of the BMAL1-CLOCK (NPAS2) heterodimer to the E-box of the Per2 promoter region. Negative feedback of PER protein on this promoter subsequently represses transcription. Other circadian transcription regulators, particularly E4BP4 and DEC2, regulate the amplitude and phase of Per2 expression rhythms. Moreover, a direct repeat of E-box-like (EE) elements in the Per2 promoter is required for its cell-autonomous circadian rhythm. However, the detailed mechanism for repression of the two core sequences of the EE element in the Per2 promoter region is unknown. Here, we show that E4BP4 binds to the Per2 EE element with DEC2 to repress transcription and identify the DEC2-E4BP4 heterodimer as a key repressor of the tightly interlocked Per2 feedback loop in the mammalian circadian oscillator. Our results suggest an additional modulatory mechanism for tuning of the phase of cell-autonomous Per2 gene expression cycling.
哺乳动物中生物钟基因表达的昼夜节律振荡基于Period（Per）和Bmal1相互连接的转录/翻译反馈环。Per反馈环通过BMAL1-CLOCK（NPAS2）异二聚体直接结合到Per2启动子区域的E-box来启动转录。PER蛋白对该启动子的负反馈随后抑制转录。其他昼夜节律转录调节因子，特别是E4BP4和DEC2，调节Per2表达节律的幅度和相位。此外，Per2启动子中E-box样（EE）元件的直接重复对于其细胞自主昼夜节律是必需的。然而，Per2启动子区域中EE元件的两个核心序列的抑制详细机制尚不清楚。在这里，我们表明E4BP4与DEC2结合到Per2 EE元件以抑制转录，并确定DEC2-E4BP4异二聚体是哺乳动物昼夜节律振荡器中紧密连锁的Per2反馈环的关键抑制因子。我们的结果表明了一种用于调节细胞自主Per2基因表达循环相位的额外调节机制。
