Journal
CELL REPORTS
Volume 14, Issue 4, Pages 823-834Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2015.12.076
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Funding
- National Science Foundation of China [31230049, 31171343]
- Ministry of Science and Technology [2013CB945203]
- priority Academic Development of Jiangsu Higher Education Institutions
- NIH [GM068496]
- Welch Foundation [I-1560]
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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.
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