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Cell Rep. 2016 Feb 2;14(4):823-834. doi: 10.1016/j.celrep.2015.12.076. Epub 2016 Jan 14.

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

Author information

1
Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Nanjing University, 12 Xuefu Road, Pukou District, Nanjing 210061, China.
2
Cambridge-Suda Genomic Research Center, Soochow University, 199 Renai Road, Suzhou 215123, China.
3
College of Pharmaceutical Sciences, Soochow University, 199 Renai Road, Suzhou 215123, China.
4
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: yi.liu@utsouthwestern.edu.
5
Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Nanjing University, 12 Xuefu Road, Pukou District, Nanjing 210061, China; Cambridge-Suda Genomic Research Center, Soochow University, 199 Renai Road, Suzhou 215123, China; Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai 200433, China. Electronic address: yingxu@suda.edu.cn.

Abstract

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.

PMID:
26776516
DOI:
10.1016/j.celrep.2015.12.076
[Indexed for MEDLINE]
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