Accumulating evidence points to a significant link between disrupted circadian rhythms and neuronal disfunctions, though the molecular mechanisms underlying this connection are virtually unexplored. The transcript Homer1a, an immediate early gene related to postsynaptic signaling, has been demonstrated to exhibit robust circadian oscillation in the brain, which supports the hypothesis that Homer1a mediates the communication between circadian inputs and neuronal activity. Here, we determined how the circadian clock is implicated in Homer1a gene regulation by using circadian clock Bmal1-mutant mice either in the presence or absence of stress stimulation. The Homer1 gene generates multiple transcripts, but only the short variant Homer1a responds to acute stress with sleep deprivation (SD) in mice. Chromatin immunoprecipitation assays revealed that both transcription factor CREB and the circadian clock component BMAL1 bind to the Homer1 promoter in mouse brain. Importantly, circadian Homer1a gene expression is unaltered in the absence of BMAL1, while its immediate early response to SD relies on BMAL1. Deletion of Bmal1 results in attenuated CREB activity in mouse brain, which appears to contribute to decreased expression of Homer1a in response to SD. In conclusion, Homer1a undergoes bimodal control by the circadian clock and CREB.

中文翻译：

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Homer1a经历了CREB和生物钟的双峰转录调控。

越来越多的证据表明，昼夜节律紊乱与神经元功能障碍之间存在着重要的联系，尽管实际上尚未探究这种联系的分子机制。转录本Homer1a是与突触后信号相关的立即早期基因，已被证明在大脑中表现出强劲的昼夜节律振荡，这支持了Homer1a介导昼夜节律输入与神经元活动之间的交流这一假设。在这里，我们确定了在有或没有应激刺激的情况下，通过使用昼夜节律Bmal1-突变小鼠，昼夜节律如何与Homer1a基因调控有关。Homer1基因产生多种转录本，但是只有短的变体Homer1a对小鼠的急性应激具有睡眠剥夺（SD）的反应。染色质免疫沉淀试验表明，转录因子CREB和生物钟组件BMAL1均与小鼠脑内的Homer1启动子结合。重要的是，在不存在BMAL1的情况下，昼夜节律Homer1a基因的表达不会改变，而其对SD的立即早期反应则依赖于BMAL1。Bmal1的删除导致小鼠脑中CREB活性减弱，这似乎有助于响应SD导致Homer1a表达降低。总之，Homer1a受到昼夜节律和CREB的双峰控制。Bmal1的删除导致小鼠脑中CREB活性减弱，这似乎有助于响应SD导致Homer1a表达降低。总之，Homer1a受到昼夜节律和CREB的双峰控制。Bmal1的删除导致小鼠脑中CREB活性减弱，这似乎有助于响应SD导致Homer1a表达降低。总之，Homer1a受到昼夜节律和CREB的双峰控制。