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

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

Research output: Contribution to journalArticle

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)823-834
Number of pages12
JournalCell Reports
Volume14
Issue number4
DOIs
StatePublished - Feb 2 2016

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Shi, G., Xie, P., Qu, Z., Zhang, Z., Dong, Z., An, Y., Xing, L., Liu, Z., Dong, Y., Xu, G., Yang, L., Liu, Y., & Xu, Y. (2016). Distinct Roles of HDAC3 in the Core Circadian Negative Feedback Loop Are Critical for Clock Function. Cell Reports, 14(4), 823-834. https://doi.org/10.1016/j.celrep.2015.12.076