Aguilar-Arnal Lorena, Katada Sayako, Orozco-Solis Ricardo, Sassone-Corsi Paolo
Center for Epigenetics and Metabolism, U904 INSERM, Department of Biological Chemistry, School of Medicine University of California, Irvine, Irvine, California, USA.
Nat Struct Mol Biol. 2015 Apr;22(4):312-8. doi: 10.1038/nsmb.2990. Epub 2015 Mar 9.
The circadian clock controls the transcription of hundreds of 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 with cyclic trimethylation of histone H3 Lys4 (H3K4) at circadian promoters. Remarkably, in mouse liver circadian H3K4 trimethylation is modulated by SIRT1, an 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 it affects the methyltransferase activity of MLL1. Moreover, H3K4 methylation at clock-controlled-gene promoters is influenced by pharmacological or genetic inactivation of SIRT1. Finally, levels of MLL1 acetylation and H3K4 trimethylation at circadian gene promoters depend on NAD(+) circadian levels. These findings reveal a previously unappreciated regulatory pathway between energy metabolism and histone methylation.
昼夜节律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（MLL1）协调CLOCK - BMAL1激活复合物与染色质的结合，这一事件与昼夜节律启动子处组蛋白H3赖氨酸4（H3K4）的循环三甲基化相关。值得注意的是，在小鼠肝脏中，昼夜节律性的H3K4三甲基化受SIRT1调节，SIRT1是一种参与时钟控制的NAD⁺依赖性脱乙酰酶。我们发现哺乳动物的MLL1在两个保守残基K1130和K1133处被乙酰化。值得注意的是，MLL1的乙酰化是周期性的，受时钟和SIRT1控制，并且它影响MLL1的甲基转移酶活性。此外，时钟控制基因启动子处的H3K4甲基化受SIRT1的药理学或遗传学失活影响。最后，昼夜节律基因启动子处的MLL1乙酰化水平和H3K4三甲基化水平取决于NAD⁺的昼夜节律水平。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。
