NAD(+)-SIRT1 control of H3K4 trimethylation through circadian deacetylation of MLL1.
NAD(+)-SIRT1 control of H3K4 trimethylation through circadian deacetylation of MLL1.
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DOI：
10.1038/nsmb.2990
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发表时间：
2015-04
影响因子：
16.8
通讯作者：
Sassone-Corsi P
中科院分区：
文献类型：
--
作者：
Aguilar-Arnal L;Katada S;Orozco-Solis R;Sassone-Corsi P
生物钟通过特定的染色质重塑事件控制数百个基因的转录。组蛋白甲基转移酶混合谱系白血病1（MLL 1）协调CLOCK-BMAL 1激活剂复合物向染色质的募集，这是与昼夜节律启动子处的环状H3 K4三甲基化相关的事件。值得注意的是，在小鼠肝脏中，昼夜节律H3 K4 me 3由SIRT 1调节，SIRT 1是一种参与时钟控制的NAD+依赖性脱乙酰酶。我们发现哺乳动物MLL 1在两个保守残基K1130和K1133处被乙酰化。值得注意的是，MLL 1乙酰化是循环的，由时钟和SIRT 1控制，并影响MLL 1的甲基转移酶活性。此外，在时钟控制的基因启动子的H3 K4甲基化受到SIRT 1的药理学或遗传失活的影响。最后，昼夜节律基因启动子处的MLL 1乙酰化和H3 K4 me 3水平取决于NAD+昼夜节律水平。这些发现揭示了能量代谢和组蛋白甲基化之间以前未被认识的调节途径。
The circadian clock controls the transcription of hundred genes through specific chromatin remodeling events. The histone methyltransferase Mixed-Lineage Leukemia 1 (MLL1) coordinates recruitment of CLOCK–BMAL1 activator complexes to chromatin, an event associated to cyclic H3K4 tri-methylation at circadian promoters. Remarkably, in mouse liver circadian H3K4me3 is modulated by SIRT1, a NAD+ dependent deacetylase involved in clock control. We show that mammalian MLL1 is acetylated at two conserved residues, K1130 and K1133. Notably, MLL1 acetylation is cyclic, controlled by the clock and by SIRT1, and impacts the methyltransferase activity of MLL1. Moreover, H3K4 methylation at clock-controlled gene promoters is influenced by pharmacological or genetic inactivation of SIRT1. Finally, MLL1 acetylation and H3K4me3 levels at circadian gene promoters depend on NAD+ circadian levels. These findings reveal a previously unappreciated regulatory pathway between energy metabolism and histone methylation.