CLOCK-mediated acetylation of BMAL1 controls circadian function

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Abstract
The circadian regulator CLOCK has histone acetyltransferase (HAT) activity that contributes to chromatin-remodelling events during circadian control of gene expression. Here, CLOCK is shown to acetylate its heterodimerization partner BMAL1, a step which facilitates recruitment of CRY1 and promotes transcriptional repression. 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.