Phosphorylation of LSD1 by PKCα Is Crucial for Circadian Rhythmicity and Phase Resetting
Phosphorylation of LSD1 by PKCα Is Crucial for Circadian Rhythmicity and Phase Resetting
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DOI：
10.1016/j.molcel.2014.01.028
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发表时间：
2014-03-06
期刊：
影响因子：
16
通讯作者：
Baek, Sung Hee
中科院分区：
文献类型：
--
作者：
Nam, Hye Jin;Boo, Kyungjin;Baek, Sung Hee
生物钟是一种自我维持的振荡器，控制着日常的节奏。对于适当的昼夜基因表达，染色质结构的动态变化是重要的。虽然染色质修饰剂已被证明在昼夜节律基因表达中发挥作用，但在生物体水平上昼夜节律信号调节的染色质修饰剂的体内作用仍有待阐明。在这里，我们提供的证据表明，赖氨酸特异性脱甲基酶1（LSD 1）被蛋白激酶C α（PKC α）以昼夜节律的方式磷酸化，磷酸化的LSD 1与CLOCK：BMAL 1形成复合物，以促进E盒介导的转录激活。携带磷酸化缺陷型Lsd 1（SA/SA）等位基因的敲入小鼠表现出运动行为的昼夜节律改变，核心时钟基因的节律表达减弱，昼夜时钟的相位重置受损。这些数据表明LSD 1是分子生物钟振荡器的关键组成部分，在生物钟的节律性和相位重置中起着关键作用。
The circadian clock is a self-sustaining oscillator that controls daily rhythms. For the proper circadian gene expression, dynamic changes in chromatin structure are important. Although chromatin modifiers have been shown to play a role in circadian gene expression, the in vivo role of circadian signal-modulated chromatin modifiers at an organism level remains to be elucidated. Here, we provide evidence that the lysine-specific demethylase 1 (LSD1) is phosphorylated by protein kinase C alpha (PKC alpha) in a circadian manner and the phosphorylated LSD1 forms a complex with CLOCK:BMAL1 to facilitate E-box-mediated transcriptional activation. Knockin mice bearing phosphorylation-defective Lsd1(SA/SA) alleles exhibited altered circadian rhythms in locomotor behavior with attenuation of rhythmic expression of core clock genes and impaired phase resetting of circadian clock. These data demonstrate that LSD1 is a key component of the molecular circadian oscillator, which plays a pivotal role in rhythmicity and phase resetting of the circadian clock.