CLOCK-mediated acetylation of BMAL1 controls circadian function. Nature

Department of Pharmacology, School of Medicine, University of California Irvine, Irvine 92697-4625, California, USA.
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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    • "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.
    Gene 08/2015; 574(2). DOI:10.1016/j.gene.2015.08.030 · 2.14 Impact Factor
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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.
    Frontiers in Molecular Neuroscience 08/2014; 7:69. DOI:10.3389/fnmol.2014.00069 · 4.08 Impact Factor
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    • "Primary IP against Flag-SIRT1 revealed an interaction with CLOCK, and a secondary IP with HA-SIRT6 also revealed an interaction with CLOCK (Figure 4F), which is in keeping with evidence showing that these two sirtuins independently interact with the clock machinery. Lastly, SIRT1 has been shown to deacetylate BMAL1 at lysine 537 (Hirayama et al., 2007; Nakahata et al., 2008). Whereas SIRT1 readily deacetylates BMAL1, SIRT6 is not able to do so (Figure 4G), highlighting different mechanisms of action of these two sirtuins that reside in partitioned subcellular clock complexes. "
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    ABSTRACT: Circadian rhythms are intimately linked to cellular metabolism. Specifically, the NAD(+)-dependent deacetylase SIRT1, the founding member of the sirtuin family, contributes to clock function. Whereas SIRT1 exhibits diversity in deacetylation targets and subcellular localization, SIRT6 is the only constitutively chromatin-associated sirtuin and is prominently present at transcriptionally active genomic loci. Comparison of the hepatic circadian transcriptomes reveals that SIRT6 and SIRT1 separately control transcriptional specificity and therefore define distinctly partitioned classes of circadian genes. SIRT6 interacts with CLOCK:BMAL1 and, differently from SIRT1, governs their chromatin recruitment to circadian gene promoters. Moreover, SIRT6 controls circadian chromatin recruitment of SREBP-1, resulting in the cyclic regulation of genes implicated in fatty acid and cholesterol metabolism. This mechanism parallels a phenotypic disruption in fatty acid metabolism in SIRT6 null mice as revealed by circadian metabolome analyses. Thus, genomic partitioning by two independent sirtuins contributes to differential control of circadian metabolism.
    Cell 07/2014; 158(3):659-72. DOI:10.1016/j.cell.2014.06.050 · 32.24 Impact Factor
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