Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology.
Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology.
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DOI：
10.1038/nature07541
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发表时间：
2008-12-18
期刊：
影响因子：
64.8
通讯作者：
Lazar, Mitchell A.
中科院分区：
文献类型：
--
作者：
Alenghat, Theresa;Meyers, Katherine;Mullican, Shannon E.;Leitner, Kirstin;Adeniji-Adele, Adetoun;Avila, Jacqueline;Bucan, Maja;Ahima, Rexford S.;Kaestner, Klaus H.;Lazar, Mitchell A.
生物钟基因上组蛋白乙酰化的节律性变化表明，基因表达的时间调控受染色质修饰的调节。此外，近期研究表明生物钟与代谢生理之间存在关键联系。核受体辅阻遏物1（NCoR）作为染色质修饰酶组蛋白去乙酰化酶3（HDAC3）的激活亚基发挥作用。缺乏NCoR是致命的，因此尚不清楚NCoR，尤其是其对HDAC3的调节，对成年哺乳动物生理是否至关重要。在此我们表明，在小鼠中特异性地基因破坏NCoR - HDAC3相互作用会导致生物钟基因的异常调节，并造成异常的昼夜节律行为。这些小鼠由于能量消耗增加，也更瘦且对胰岛素更敏感。出乎意料的是，体内功能性NCoR - HDAC3复合物的缺失并不会导致已知分解代谢基因的持续升高，而是显著改变了几种代谢基因的振荡模式，这表明代谢的昼夜节律调节对正常的能量平衡至关重要。这些发现表明，NCoR对HDAC3的激活是生物钟和代谢生理的表观遗传调控的一个节点。
Rhythmic changes in histone acetylation at circadian clock genes suggest that temporal modulation of gene expression is regulated by chromatin modifications. Furthermore, recent studies demonstrate a critical relationship between circadian and metabolic physiology. The Nuclear Receptor Co-Repressor 1 (NCoR) functions as an activating subunit for the chromatin modifying enzyme histone deacetylase 3 (HDAC3). Lack of NCoR is incompatible with life, and hence it is unknown whether NCoR, and particularly its regulation of HDAC3, is critical for adult mammalian physiology. Here we show that specific, genetic disruption of the NCoR-HDAC3 interaction in mice causes aberrant regulation of clock genes and results in abnormal circadian behavior. These mice are also leaner and more insulin sensitive due to increased energy expenditure. Unexpectedly, loss of a functional NCoR-HDAC3 complex in vivo does not lead to sustained elevations of known catabolic genes, but rather significantly alters the oscillatory patterns of several metabolic genes, demonstrating that circadian regulation of metabolism is critical for normal energy balance. These findings indicate that activation of HDAC3 by NCoR is a nodal point in the epigenetic regulation of circadian and metabolic physiology.
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影响因子：
5.3
作者：
Guenther, MG;Barak, O;Lazar, MA
通讯作者：
Lazar, MA
影响因子：
4.5
作者：
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作者：
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影响因子：
64.5
作者：
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通讯作者：
Schibler, U
影响因子：
64.5
作者：
Jepsen, K;Hermanson, O;Rosenfeld, MG
通讯作者：
Rosenfeld, MG