Editors' ChoiceCircadian Rhythms

Against the CLOCK

Science Signaling  29 Jul 2008:
Vol. 1, Issue 30, pp. ec270
DOI: 10.1126/scisignal.130ec270

The feedback loop that controls the circadian clock includes the proteins CLOCK and BMAL1, which form a complex that binds to regulatory elements of circadian clock genes and drives their transcription. Two such genes are Period (Per) and Cryptochrome (Cry), whose products PER and CRY accumulate and then inhibit the activity of CLOCK-BMAL1. This feedback loop is entrained in the brain by light-dark cycles, but feeding behavior also seems to play some role. CLOCK was recently characterized as a histone acetyltransferase (HAT), which acetylates histone proteins to facilitate gene transcription, but CLOCK also acetylates nonhistone proteins, including BMAL1. Two groups have now identified the NAD+-dependent protein SIRT1 as the histone deacetylase (HDAC) that counteracts CLOCK. Asher et al. found that the abundance of SIRT1 was regulated in a circadian manner in mouse embryonic fibroblasts; that SIRT1 was necessary for the circadian expression of circadian clock genes; and that SIRT1 bound to CLOCK-BMAL1 and PER2 in a circadian manner. SIRT1 also deacetylated PER2, which promoted its degradation. Nakahata et al. found that the HDAC activity, but not the abundance, of SIRT1 was under circadian control and that knockout of Sirt1 changed the circadian expression of circadian clock genes. SIRT1 was found in a chromatin complex with CLOCK-BMAL1 at the promoter of the circadian clock gene Dbp, where it contributed to the cyclical acetylation-deacetylation of histone H3 and BMAL1. As for PER2, deacetylation of BMAL1 led to its degradation. In commentary, Belden and Dunlap focus more on the similarities than on the differences between these two studies. Because its activity is dependent on NAD+ and thus is affected by metabolism, SIRT1 may be the link that enables metabolic control of the circadian clock.

G. Asher, D. Gatfield, M. Stratmann, H. Reinke, C. Dibner, F. Kreppel, R. Mostoslavsky, F. W. Alt, U. Schibler, SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134, 317-328 (2008). [Online Journal]

Y. Nakahata, M. Kaluzova, B. Grimaldi, S. Sahar, J. Hirayama, D. Chen, L. P. Guarente, P. Sassone-Corsi, The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134, 329-340 (2008). [Online Journal]

W. J. Belden, J. C. Dunlap, SIRT1 is a circadian deacetylase for core clock components. Cell 134, 212-214 (2008). [Online Journal]