1. Department of Pharmacology, School of Medicine, University of California, Irvine, 92697-4625 Irvine, California, USA
2. 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).

Abstract

Regulation of circadian physiology relies on the interplay of interconnected transcriptional–translational feedback loops^{1, 2}. The CLOCK–BMAL1 complex activates clock-controlled genes, including cryptochromes (Crys), the products of which act as repressors by interacting directly with CLOCK–BMAL1^{3, 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 components^{6, 7} is crucial for the circadian machinery.

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