Regulation of circadian physiology relies on the interplay of interconnected transcriptional–translational feedback loops1,2. The CLOCK–BMAL1 complex activates clock-controlled genes, including cryptochromes (Crys), the products of which act as repressors by interacting directly with CLOCK–BMAL13,4. We have demonstrated that CLOCK possesses intrinsic histone acetyltransferase activity and that this enzymatic function contributes to chromatin-remodelling events implicated in circadian control of gene expression5. Here we show that CLOCK also acetylates a non-histone substrate: its own partner, BMAL1, is specifically acetylated on a unique, highly conserved Lys 537 residue. BMAL1 undergoes rhythmic acetylation in mouse liver, with a timing that parallels the downregulation of circadian transcription of clock-controlled genes. BMAL1 acetylation facilitates recruitment of CRY1 to CLOCK–BMAL1, thereby promoting transcriptional repression. Importantly, ectopic expression of a K537R-mutated BMAL1 is not able to rescue circadian rhythmicity in a cellular model of peripheral clock. These findings reveal that the enzymatic interplay between two clock core components6,7 is crucial for the circadian machinery.
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We thank J. S. Steffan, C. A. Bradfield, G. T. van der Horst, F. Tamanini, M. Doi, T. Takumi and T. Todo for discussions and sharing of reagents. We also thank M. Kaluzova, D. Gauthier, D. Mishra Prasad and all colleagues in the Sassone-Corsi laboratory for discussions and help. This work was supported by grants from the Cancer Research Coordinating Committee of the University of California and from the National Institutes of Health to P.S.-C.
Author Contributions J.H., S.S., B.G. and P.S.-C. designed the research; J.H., S.S., B.G., T.T., K.T. and Y.N. performed the experiments; J.H., S.S., B.G., T.T. and P.S.-C. analysed the data; and J.H. and P.S.-C. wrote the paper.
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Hirayama, J., Sahar, S., Grimaldi, B. et al. CLOCK-mediated acetylation of BMAL1 controls circadian function. Nature 450, 1086–1090 (2007). https://doi.org/10.1038/nature06394
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