CLOCK-mediated acetylation of BMAL1 controls circadian function.
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.
Hirayama
Jun
J
Department of Pharmacology, School of Medicine, University of California Irvine, Irvine 92697-4625, California, USA.
Sahar
Saurabh
S
Grimaldi
Benedetto
B
Tamaru
Teruya
T
Takamatsu
Ken
K
Nakahata
Yasukazu
Y
Sassone-Corsi
Paolo
P
D056930:ARNTL Transcription Factors; D000107:Acetylation; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D056926:CLOCK Proteins; D002940:Circadian Rhythm / Q000502:physiology*; D056931:Cryptochromes; D005420:Flavoproteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D051379:Mice; D013379:Substrate Specificity; D015534:Trans-Activators / Q000378:metabolism*
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D056931:Cryptochromes; D005420:Flavoproteins; D008239:Lysine; D015534:Trans-Activators; C538961:Bmal1 protein, mouse; C538964:Cry1 protein, mouse; C538944:Clock protein, mouse