Chromatin remodeling and circadian control: master regulator CLOCK is an enzyme.
The molecular machinery that governs circadian rhythmicity is based on clock gene products organized in regulatory feedback loops. Recently, we have shown that CLOCK, a master circadian regulator, has histone acetyltransferase activity essential for clock gene expression. The Lys-14 residue of histone H3 is a preferential target of CLOCK-mediated acetylation. As the role of chromatin remodeling in eukaryotic transcription is well recognized, this finding identified unforeseen links between histone acetylation and cellular physiology. Indeed, we have shown that the enzymatic function of CLOCK drives circadian control. We reasoned that CLOCK's acetyltransferase activity could also target nonhistone proteins, a feature displayed by other HATs. Indeed, CLOCK also acetylates a nonhistone substrate: its own partner, BMAL1. This protein undergoes rhythmic acetylation in the mouse liver, with a timing that parallels the down-regulation of circadian transcription of clock-controlled genes. BMAL1 is specifically acetylated on a unique, highly conserved Lys-537 residue. This acetylation facilitates recruitment of the repressor CRY1 to BMAL1, indicating that CLOCK may intervene in negative circadian regulation. Our findings reveal that the enzymatic interplay between two clock core components is crucial for the circadian machinery.
Grimaldi
B
B
Department of Pharmacology, School of Medicine, University of California, Irvine, California 92697, USA.
Nakahata
Y
Y
Sahar
S
S
Kaluzova
M
M
Gauthier
D
D
Pham
K
K
Patel
N
N
Hirayama
J
J
Sassone-Corsi
P
P
D056930:ARNTL Transcription Factors; D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology; D056926:CLOCK Proteins; D042002:Chromatin Assembly and Disassembly / Q000235:genetics / Q000502:physiology*; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D051548:Histone Acetyltransferases / Q000235:genetics / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D013493:Suprachiasmatic Nucleus / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D051548:Histone Acetyltransferases; D015534:Trans-Activators; C538960:BMAL1 protein, human; C538961:Bmal1 protein, mouse; C538943:CLOCK protein, human; C538944:Clock protein, mouse