Article

CLOCK-mediated acetylation of BMAL1 controls circadian function.

Department of Pharmacology, School of Medicine, University of California Irvine, Irvine 92697-4625, California, USA.
Nature (impact factor: 36.28). 01/2008; 450(7172):1086-90. DOI:10.1038/nature06394 pp.1086-90
Source: PubMed

ABSTRACT Regulation of circadian physiology relies on the interplay of interconnected transcriptional-translational feedback loops. The CLOCK-BMAL1 complex activates clock-controlled genes, including cryptochromes (Crys), the products of which act as repressors by interacting directly with CLOCK-BMAL1. 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. 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 is crucial for the circadian machinery.

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Keywords

BMAL1 acetylation facilitates recruitment
 
BMAL1 undergoes rhythmic acetylation
 
cellular model
 
chromatin-remodelling events
 
circadian control
 
circadian machinery
 
circadian physiology
 
circadian transcription
 
clock core components
 
CLOCK possesses intrinsic histone acetyltransferase activity
 
CLOCK-BMAL1 complex activates clock-controlled genes
 
clock-controlled genes
 
conserved Lys 537 residue
 
ectopic expression
 
gene expression
 
non-histone substrate
 
peripheral clock
 
rescue circadian rhythmicity
 
transcriptional repression
 
transcriptional-translational feedback loops