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CLOCK-mediated acetylation of BMAL1 controls circadian function

Abstract

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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Figure 1: Circadian regulator BMAL1 is acetylated.
Figure 2: A single lysine of BMAL1 is acetylated.
Figure 3: Acetylation of BMAL1 is essential to rescue the circadian rhythmicity in BMAL1-deficient cells.
Figure 4: Acetylation of BMAL1 facilitates CRY1-mediated repression.

References

  1. Dunlap, J. C. Molecular bases for circadian clocks. Cell 96, 271–290 (1999)

    CAS  Article  Google Scholar 

  2. Reppert, S. M. & Weaver, D. R. Coordination of circadian timing in mammals. Nature 418, 935–941 (2002)

    CAS  Article  ADS  Google Scholar 

  3. King, D. P. & Takahashi, J. S. Molecular genetics of circadian rhythms in mammals. Annu. Rev. Neurosci. 23, 713–742 (2000)

    CAS  Article  Google Scholar 

  4. Young, M. W. & Kay, S. A. Time zones: a comparative genetics of circadian clocks. Nature Rev. Genet. 2, 702–715 (2001)

    CAS  Article  Google Scholar 

  5. Doi, M., Hirayama, J. & Sassone-Corsi, P. Circadian regulator CLOCK is a histone acetyltransferase. Cell 125, 497–508 (2006)

    CAS  Article  Google Scholar 

  6. King, D. P. et al. Positional cloning of the mouse circadian clock gene. Cell 89, 641–653 (1997)

    CAS  Article  Google Scholar 

  7. Bunger, M. K. et al. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103, 1009–1017 (2000)

    CAS  Article  Google Scholar 

  8. Cermakian, N. & Sassone-Corsi, P. Multilevel regulation of the circadian clock. Nature Rev. Mol. Cell Biol. 1, 59–67 (2000)

    CAS  Article  Google Scholar 

  9. Hirayama, J. & Sassone-Corsi, P. Structural and functional features of transcription factors controlling the circadian clock. Curr. Opin. Genet. Dev. 15, 548–556 (2005)

    CAS  Article  Google Scholar 

  10. Belden, W. J., Loros, J. J. & Dunlap, J. C. CLOCK leaves its mark on histones. Trends Biochem. Sci. 31, 610–613 (2006)

    CAS  Article  Google Scholar 

  11. Glozak, M. A., Sengupta, N., Zhang, X. & Seto, E. Acetylation and deacetylation of non-histone proteins. Gene 363, 15–23 (2005)

    CAS  Article  Google Scholar 

  12. Zhang, K. & Dent, S. Y. Histone modifying enzymes and cancer: going beyond histones. J. Cell. Biochem. 96, 1137–1148 (2005)

    CAS  Article  Google Scholar 

  13. Gekakis, N. et al. Role of the CLOCK protein in the mammalian circadian mechanism. Science 280, 1564–1569 (1998)

    CAS  Article  ADS  Google Scholar 

  14. Hogenesch, J. B. et al. The basic helix-loop-helix-PAS protein MOP9 is a brain-specific heterodimeric partner of circadian and hypoxia factors. J. Neurosci. 20, RC83 (2000)

    CAS  Article  Google Scholar 

  15. Lee, C., Etchegaray, J. P., Cagampang, F. R., Loudon, A. S. & Reppert, S. M. Posttranslational mechanisms regulate the mammalian circadian clock. Cell 107, 855–867 (2001)

    CAS  Article  Google Scholar 

  16. Matsuo, T. et al. Control mechanism of the circadian clock for timing of cell division in vivo . Science 302, 255–259 (2003)

    CAS  Article  ADS  Google Scholar 

  17. van der Horst, G. T. et al. Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398, 627–630 (1999)

    CAS  Article  ADS  Google Scholar 

  18. Kume, K. et al. mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 98, 193–205 (1999)

    CAS  Article  Google Scholar 

  19. Jin, X. et al. A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock. Cell 96, 57–68 (1999)

    CAS  Article  Google Scholar 

  20. Cardone, L. et al. Circadian clock control by SUMOylation of BMAL1. Science 309, 1390–1394 (2005)

    CAS  Article  ADS  Google Scholar 

  21. Shalizi, A. et al. A calcium-regulated MEF2 sumoylation switch controls postsynaptic differentiation. Science 311, 1012–1017 (2006)

    CAS  Article  ADS  Google Scholar 

  22. Kondratov, R. V. et al. BMAL1-dependent circadian oscillation of nuclear CLOCK: posttranslational events induced by dimerization of transcriptional activators of the mammalian clock system. Genes Dev. 17, 1921–1932 (2003)

    CAS  Article  Google Scholar 

  23. Nagoshi, E. et al. Circadian gene expression in individual fibroblasts: cell-autonomous and self-sustained oscillators pass time to daughter cells. Cell 119, 693–705 (2004)

    CAS  Article  Google Scholar 

  24. Sato, T. K. et al. Feedback repression is required for mammalian circadian clock function. Nature Genet. 38, 312–319 (2006)

    CAS  Article  Google Scholar 

  25. Griffin, E. A., Staknis, D. & Weitz, C. J. Light-independent role of CRY1 and CRY2 in the mammalian circadian clock. Science 286, 768–771 (1999)

    CAS  Article  Google Scholar 

  26. Chaves, I. et al. Functional evolution of the photolyase/cryptochrome protein family: importance of the C terminus of mammalian CRY1 for circadian core oscillator performance. Mol. Cell. Biol. 26, 1743–1753 (2006)

    CAS  Article  Google Scholar 

  27. DeBruyne, J. P., Weaver, D. R. & Reppert, S. M. Peripheral circadian oscillators require CLOCK. Curr. Biol. 17, R538–R539 (2007)

    CAS  Article  Google Scholar 

  28. Sterner, D. E. & Berger, S. L. Acetylation of histones and transcription-related factors. Microbiol. Mol. Biol. Rev. 64, 435–459 (2000)

    CAS  Article  Google Scholar 

  29. Kiyohara, Y. B. et al. The BMAL1 C terminus regulates the circadian transcription feedback loop. Proc. Natl Acad. Sci. USA 103, 10074–10079 (2006)

    CAS  Article  ADS  Google Scholar 

  30. Yoo, S. H. et al. A noncanonical E-box enhancer drives mouse Period2 circadian oscillations in vivo . Proc. Natl Acad. Sci. USA 102, 2608–2613 (2005)

    CAS  Article  ADS  Google Scholar 

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Acknowledgements

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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Correspondence to Paolo Sassone-Corsi.

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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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