title: Distinct Roles of HDAC3 in the Core Circadian Negative Feedback Loop Are Critical for Clock Function.
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.
authors.affiliation: 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.
authors.forename: Guangsen
authors.initials: G
authors.lastname: Shi
authors.affiliation: 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.
authors.forename: Pancheng
authors.initials: P
authors.lastname: Xie
authors.affiliation: 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.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Qu
authors.affiliation: 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.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Dong
authors.affiliation: 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: An
authors.affiliation: Cambridge-Suda Genomic Research Center, Soochow University, 199 Renai Road, Suzhou 215123, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Xing
authors.affiliation: Cambridge-Suda Genomic Research Center, Soochow University, 199 Renai Road, Suzhou 215123, China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Cambridge-Suda Genomic Research Center, Soochow University, 199 Renai Road, Suzhou 215123, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Dong
authors.affiliation: College of Pharmaceutical Sciences, Soochow University, 199 Renai Road, Suzhou 215123, China.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Xu
authors.affiliation: Cambridge-Suda Genomic Research Center, Soochow University, 199 Renai Road, Suzhou 215123, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: yi.liu@utsouthwestern.edu.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism; D000818:Animals; D057906:Circadian Clocks; D056931:Cryptochromes / Q000378:metabolism; D024721:E-Box Elements; D025461:Feedback, Physiological; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D059748:Proteolysis; D000099186:Histone Deacetylase 3
chemical_list: D056930:ARNTL Transcription Factors; D056931:Cryptochromes; D006655:Histone Deacetylases; D000099186:Histone Deacetylase 3; C538961:Bmal1 protein, mouse; C538964:Cry1 protein, mouse