S6K1 controls adiponectin expression by inducing a transcriptional switch: BMAL1-to-EZH2
2
조회
0
다운로드
0
인용
0
참고문헌
초록
Adiponectin (encoded by Adipoq), a fat-derived hormone, alleviates risk factors associated with metabolic disorders. Although many transcription factors are known to control adiponectin expression, the mechanism underlying its fluctuation with regard to metabolic status remains unclear. Here, we show that ribosomal protein S6 kinase 1 (S6K1) controls adiponectin expression by inducing a transcriptional switch between two transcriptional machineries, BMAL1 and EZH2. Active S6K1 induced a suppressive histone code cascade, H2BS36p-EZH2-H3K27me3, leading to suppression of adiponectin expression. Moreover, active S6K1 phosphorylated BMAL1, an important transcription factor regulating the circadian clock system, at serine 42, which led to its dissociation from the Adipoq promoter region. This response resulted in EZH2 recruitment and subsequent H3K27me3 modification of the Adipoq promoter. Upon fasting, inactivation of S6K1 induced the opposite transcriptional switch, EZH2-to-BMAL1, promoting adiponectin expression. Consistently, S6K1-depleted mice exhibited lower H3K27me3 levels and elevated adiponectin expression. These findings identify a novel epigenetic switch system by which S6K1 controls the production of adiponectin, which displays beneficial effects on metabolism.
Abstract
Adiponectin (encoded by Adipoq), a fat-derived hormone, alleviates risk factors associated with metabolic disorders. Although many transcription factors are known to control adiponectin expression, the mechanism underlying its fluctuation with regard to metabolic status remains unclear. Here, we show that ribosomal protein S6 kinase 1 (S6K1) controls adiponectin expression by inducing a transcriptional switch between two transcriptional machineries, BMAL1 and EZH2. Active S6K1 induced a suppressive histone code cascade, H2BS36p-EZH2-H3K27me3, leading to suppression of adiponectin expression. Moreover, active S6K1 phosphorylated BMAL1, an important transcription factor regulating the circadian clock system, at serine 42, which led to its dissociation from the Adipoq promoter region. This response resulted in EZH2 recruitment and subsequent H3K27me3 modification of the Adipoq promoter. Upon fasting, inactivation of S6K1 induced the opposite transcriptional switch, EZH2-to-BMAL1, promoting adiponectin expression. Consistently, S6K1-depleted mice exhibited lower H3K27me3 levels and elevated adiponectin expression. These findings identify a novel epigenetic switch system by which S6K1 controls the production of adiponectin, which displays beneficial effects on metabolism.
참고문헌 (22)
- Angel, A., "A Polycomb-based switch underlying quantitative epigenetic memory", Nature, 476, pp.105~108 (2011)
- Travers, A., "Transcriptional switches : the role of mass action", Phys. Life Rev, 1, pp.57~69 (2004)
- Chandran, M., "Adiponectin : more than just another fat cell hormone?", Diabetes Care, 26, pp.2442~2450 (2003)
- Yamauchi, T., "Adiponectin receptor as a key player in healthy longevity and obesity-related diseases", Cell Metab, 17, pp.185~196 (2013)
- Liu, M., "Transcriptional and post-translational regulation of adiponectin", Biochem. J, 425, pp.41~52 (2009)
- Lipton, J. O., "The circadian protein BMAL1 regulates translation in response to s6k1-mediated phosphorylation", Cell, 161, pp.1138~1151 (2015)
- Rosner, M., "Nucleocytoplasmic localization of p70 S6K1, but not of its isoforms p85 and p31, is regulated by TSC2", mTOR, 2011, pp.30, 4509~4522
- Rosner, M., "p70 S6K1 nuclear localization depends on its mTOR-mediated phosphorylation at T389, but not on its kinase activity towards S6", Amino Acids, 42, pp.2251~2256 (2012)
- Yi, S. A., "S6K1 phosphorylation of H2B mediates EZH2 trimethylation of H3 : a determinant of early adipogenesis", Mol. Cell, 62, pp.443~452 (2016)
- Lee, J., "SETD7 drives cardiac lineage commitment through stage-specific transcriptional activation", Cell Stem Cell, 22, pp.428~444.e5 (2018)
- Kume, K., "mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop", Cell, 98, pp.193~205 (1999)
- Barnea, M., "The circadian clock machinery controls adiponectin expression", Mol. Cell. Endocrinol, 399, pp.284~287 (2015)
- Barnea, M., "Dexamethasone induces high-amplitude rhythms in preadipocytes, but hinders circadian expression in differentiated adipocytes", Chronobiol. Int, 30, pp.837~842 (2013)
- Fang, H., "Adiponectin regulation and function", Compr. Physiol, 8, pp.1031~1063 (2018)
- Castañeda, T. R., "Metabolic control by S6 kinases depends on dietary lipids", PLoS ONE, 7, pp.e32631~ (2012)
- Binsch, C., "Absence of the kinase S6k1 mimics the effect of chronic endurance exercise on glucose tolerance and muscle oxidative stress", Mol. Metab, 6, pp.1443~1453 (2017)
- Blouet, C., "Mediobasal hypothalamic p70 S6 kinase 1modulates the control of energy homeostasis", Cell Metab, 8, pp.459~467 (2008)
- Selman, C., "Ribosomal protein S6 kinase 1 signaling regulates mammalian life span", Science, 326, pp.140~144 (2009)
- Gómez-Abellán, P., "Circadian expression of adiponectin and its receptors in human adipose tissue", Endocrinology, 151, pp.115~122 (2010)
- Yang, X., "Nuclear receptor expression links the circadian clock to metabolism", Cell, 126, pp.801~810 (2006)
- Barnea, M., "High-fat diet delays and fasting advances the circadian expression of adiponectin signaling components in mouse liver", Endocrinology, 150, pp.161~168 (2009)
- Barnea, M., "High-fat diet followed by fasting disrupts circadian expression of adiponectin signaling pathway in muscle and adipose tissue", Obesity, 18, pp.230~238 (2010)