Letter Nature 450, 1086-1090 (13 December 2007) | doi:10.1038/nature06394; Received 15 July 2007; Accepted 16 October 2007
CLOCK-mediated acetylation of BMAL1 controls circadian function Jun Hirayama1, Saurabh Sahar1, Benedetto Grimaldi1, Teruya Tamaru2, Ken Takamatsu2, Yasukazu Nakahata1 & Paolo Sassone-Corsi1
Department of Pharmacology, School of Medicine, University of California, Irvine, 92697-4625 Irvine, California, USA Department of Physiology, Toho University, Faculty of Medicine, Tokyo 143-8540, Japan Correspondence to: Paolo Sassone-Corsi1 Correspondence and requests for materials should be addressed to P.S.-C. (Email: psc@uci.edu).
Top of pageRegulation 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.
Admin. Assistant to the Chair: Michele Hinojosa Office: Room 2115, Gillespie Neurosciences Research Facility, Irvine, CA 92697-4625 Admin. Asst. Tel: 949-824-2961 Admin. Asst. Email: mhinojos@uci.edu
Keywords: signal transduction, gene expression, oncogenesis, circadian clock
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Research:
Dr. Sassone-Corsi's major interest is concentrated on the mechanisms of signal transduction able to modulate nuclear functions and, in particular gene expression, chromatin remodeling and epigenetic control. These events have important consequences for the understanding of cellular proliferation, oncogenesis and differentiation. The stimulation of intracellular pathways and the activation of specific protein kinases lead to transcriptional regulation by changes in the phosphorylation state of nuclear factors. These act as final targets of different pathways and modulate expression from specific regulatory sites. The strength of these studies is particularly evident within physiological settings which have been investigated by this lab, the molecular control of circadian rhythms and the differentiation of male germ cells. Relevant Publications:
Whitmore, D., Foulkes, N. S., Str鋒le, U. and Sassone-Corsi, P. (1998) Zebrafish Clock rhythmic expression reveals independent peripheral circadian oscillators. Nature Neurosci. 1, 701-708 .
Fimia, G. M., De Cesare, D. and Sassone-Corsi, P. (1999) CBP-independent activation of CREM and CREB by the LIM-only protein ACT. Nature 398, 165-169.
Sassone-Corsi, P., Mizzen, C. A., Cheung, P., Crosio, C., Monaco, L., Jacquot, S., Hanauer, A. and Allis, C. D. (1999) Requirement of Rsk-2 for Epidermal Growth Factor-activated phosphorylation of Histone H3. Science 285, 886-891.
Whitmore, D., Foulkes, N. S. and Sassone-Corsi, P. (2000) Light acts directly on organ cells in culture to set the vertebrate circadian clock. Nature 404, 87-91
Cheung, P., Allis, C. D. and Sassone-Corsi, P. (2000) Signaling to chromatin through histone modifications. Cell 103, 263-271.
Crosio, C., Cermakian, N., Allis, D. C. and Sassone-Corsi, P. (2000) Light induces chromatin modification in cells of the mammalian circadian clock. Nature Neurosci. 3, 1241-1247
Sassone-Corsi, P. (2002) Unique chromatin remodeling and transcriptional regulation in spermatogenesis. Science 296, 2176-2178.
Pando, M. P., Morse, D., Cermakian, N. and Sassone-Corsi, P. (2002) Phenotypic Rescue of a Peripheral Clock Genetic Defect via SCN Hierarchical Dominance. Cell 110, 107-117.
Macho, B., Brancorsini, S., Fimia, G. M., Setou, M., Hirokawa, N. and Sassone-Corsi, P. (2002) CREM-Dependent Transcription in Male Germ Cells Controlled by a Kinesin. Science 298, 2388-2390.
Yanagimachi, R., Wakayama, T., Kishikawa, H., Fimia, G. M., Monaco, L. and Sassone-Corsi, P. (2004) Production of fertile offspring from genetically infertile mice. Proc. Natl. Acad. Sci. USA 101, 1691-1695.
Kimmins, S. and Sassone-Corsi, P. (2005) Chromatin remodeling and epigenetic features of germ cells. Nature 434, 583-589.
Hirayama, J., Cardone, L., Doi, M. and Sassone-Corsi, P. (2005) Common Pathways in Circadian and Cell Cycle Clocks: Light-dependent Activation of Fos/AP-1 in Zebrafish Controls CRY-1a and WEE-1. Proc. Natl. Acad. Sci. USA 102, 10194-10199. Cardone, L., Hirayama, J., Giordano, F., Tamaru, T., Palvimo, J. J. and Sassone-Corsi, P. (2005) Circadian clock control by SUMOylation of BMAL1. Science 309, 1390-1394.
Monaco, L., Kolthur-Seetharam, U., Loury, R., M閚issier-de Murcia, J., de Murcia, G. and Sassone-Corsi, P. (2005) Inhibition of Aurora-B kinase activity by poly(ADP-ribosyl)ation in response to DNA damage. Proc. Natl. Acad. Sci. USA 102, 14244-14248.
Doi, M., Hirayama, J. and Sassone-Corsi, P. (2006) Circadian regulator CLOCK is a Histone Acetyltransferase. Cell 125, 497-508.
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