CLOCK-mediated acetylation of BMAL1 controls circadian function

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 expression(5). 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.