Distinct Roles of HDAC3 in the Core Circadian Negative Feedback Loop Are Critical for Clock Function

• Main Authors: Guangsen Shi, Pancheng Xie, Zhipeng Qu, Zhihui Zhang, Zhen Dong, Yang An, Lijuan Xing, Zhiwei Liu, Yingying Dong, Guoqiang Xu, Ling Yang, Yi Liu, Ying Xu
• Format: Article
• Language: English
• Published: Elsevier 2016-02-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124715015326

In the core mammalian circadian negative feedback loop, the BMAL1-CLOCK complex activates the transcription of the genes Period (Per) and Cryptochrome (Cry). To close the negative feedback loop, the PER-CRY complex interacts with the BMAL1-CLOCK complex to repress its activity. These two processes are separated temporally to ensure clock function. Here, we show that histone deacetylase 3 (HDAC3) is a critical component of the circadian negative feedback loop by regulating both the activation and repression processes in a deacetylase activity-independent manner. Genetic depletion of Hdac3 results in low-amplitude circadian rhythms and dampened E-box-driven transcription. In subjective morning, HDAC3 is required for the efficient transcriptional activation process by regulating BMAL1 stability. In subjective night, however, HDAC3 blocks FBXL3-mediated CRY1 degradation and strongly promotes BMAL1 and CRY1 association. Therefore, these two opposing but temporally separated roles of HDAC3 in the negative feedback loop provide a mechanism for robust circadian gene expression.