CLOCK-mediated acetylation of BMAL1 controls circadian function. Nature

Toho University, Edo, Tokyo, Japan
Nature (Impact Factor: 41.46). 01/2008; 450(7172):1086-90. DOI: 10.1038/nature06394
Source: PubMed


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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    • "Second, BMAL1-CLOCK, in association with the E-boxcontaining Dbp promoter, is very unstable and shows a proteasome-dependent fluctuation (Stratmann et al., 2012). In addition, BMAL1 exhibits a robust circadian rhythm in phosphorylation profiles (Tamaru et al., 2003, 2009), and it can be acetylated by CLOCK and de-acetylated by the nicotinamide adenine dinucleotide (NAD)+-dependent SIRT1 enzyme (Hirayama et al., 2007; Nakahata et al., 2008). "
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    ABSTRACT: In the core mammalian circadian negative feedback loop, the BMAL1-CLOCK complex activates the transcription of the genes Period (Per) and Cryptochrome (Cry). To close the negative feedback loop, the PER-CRY complex interacts with the BMAL1-CLOCK complex to repress its activity. These two processes are separated temporally to ensure clock function. Here, we show that histone deacetylase 3 (HDAC3) is a critical component of the circadian negative feedback loop by regulating both the activation and repression processes in a deacetylase activity-independent manner. Genetic depletion of Hdac3 results in low-amplitude circadian rhythms and dampened E-box-driven transcription. In subjective morning, HDAC3 is required for the efficient transcriptional activation process by regulating BMAL1 stability. In subjective night, however, HDAC3 blocks FBXL3-mediated CRY1 degradation and strongly promotes BMAL1 and CRY1 association. Therefore, these two opposing but temporally separated roles of HDAC3 in the negative feedback loop provide a mechanism for robust circadian gene expression.
    Full-text · Article · Jan 2016 · Cell Reports
    • "The expression of Cry2, Clock, Arntl2, Rev-erbα, Rorγ and nocturnin were up-regulated, whereas the expression of Per1b, Per3 and Dec were down-regulated in grass carp fed with plant diets (Fig. 4). These are key clock genes controlling circadian rhythm (Emery et al., 1998; Green et al., 2007; Hirayama et al., 2007; Reppert and weaver, 2002; Vatine et al., 2011; Zylka et al., 1998), and the disruption could reset the phase. Therefore, grass carp fed with plant diets could almost continuously throughout the 24 h with reset circadian phase of feeding. "
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    ABSTRACT: Numerous studies have been focused on the replacement of fish meal by other alternative protein sources. However, little is currently known about the molecular mechanism of utilization of diets with different protein sources in fish. Grass carp is a typical herbivorous fish. To elucidate the relationship between gene expression and utilization of animal and plant diets, transcriptome sequencing was performed in grass carp fed with chironomid larvae and duckweed. Grass carp fed with duckweed had significantly higher relative length of gut than those fed with chironomid larvae. 4,435 differentially expressed genes were identified between grass carp fed with chironomid larvae and duckweed in brain, liver and gut, involved in cell proliferation and differentiation, appetite control, circadian rhythm, digestion and metabolism pathways. These pathways might play important roles in utilization of diets with different protein sources in grass carp. And the findings could provide a new insight into the replacement of fish meal in artificial diets. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Aug 2015 · Gene
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    • "This maximal activity of CLOCK/BMAL1 results in expression of CRY proteins that then repress CLOCK/BMAL1, at a time that is synchronous with the BMAL1 dephosphorylation and stabilization (Kwon et al., 2006; Dardente et al., 2007). BMAL1 acetylation by CLOCK also occurs at this time and leads to increased recruitment of CRY (Hirayama et al., 2007). CRYs themselves are good examples of substrates for sequential PTMs over the 24 h day and across the progression of the clock feedback loop (see Ubiquitination of Cryptochromes by FBXL Ubiquitin Ligases). "
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    ABSTRACT: Circadian rhythms, endogenous cycles of about 24 h in physiology, are generated by a master clock located in the suprachiasmatic nucleus of the hypothalamus and other clocks located in the brain and peripheral tissues. Circadian disruption is known to increase the incidence of various illnesses, such as mental disorders, metabolic syndrome, and cancer. At the molecular level, periodicity is established by a set of clock genes via autoregulatory translation-transcription feedback loops. This clock mechanism is regulated by post-translational modifications such as phosphorylation and ubiquitination, which set the pace of the clock. Ubiquitination in particular has been found to regulate the stability of core clock components but also other clock protein functions. Mutation of genes encoding ubiquitin ligases can cause either elongation or shortening of the endogenous circadian period. Recent research has also started to uncover roles for deubiquitination in the molecular clockwork. Here, we review the role of the ubiquitin pathway in regulating the circadian clock and we propose that ubiquitination is a key element in a clock protein modification code that orchestrates clock mechanisms and circadian behavior over the daily cycle.
    Full-text · Article · Aug 2014 · Frontiers in Molecular Neuroscience
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