Clockwork Orange is a transcriptional repressor and a new Drosophila circadian pacemaker component
Clockwork Orange is a transcriptional repressor and a new Drosophila circadian pacemaker component
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DOI：
10.1101/gad.1552607
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发表时间：
2007-07-01
影响因子：
10.5
通讯作者：
Rosbash, Michael
中科院分区：
文献类型：
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作者：
Kadener, Sebastian;Stoleru, Dan;Rosbash, Michael
许多生物使用生物钟来维持时间秩序和预测每天的环境变化。在果蝇中，主时钟基因clock促进几个关键靶基因的转录。其中两个基因产物PER和TIM抑制clk - cyc介导的转录。为了识别更多的直接CLK靶基因，我们设计了一种全基因组方法，并确定了clockwork orange(2)作为新的核心时钟成分。two编码一种转录抑制因子，与PER协同作用并抑制clk介导的激活。与这一功能相一致的是，两种突变蝇的CLK直接靶基因mRNA谱表现出高波谷值和低振幅振荡。由于行为节律性不能在持续黑暗（DD）中持续存在，对缺乏两个的果蝇的平均mRNA水平影响很小或没有影响，转录振荡幅度似乎与节律性有关。此外，突变果蝇是长周期的，与RNA谱显示的晚期抑制一致。这些发现表明，CWO优先在深夜帮助终止clk - cyc介导的直接靶基因转录，包括CWO本身。具有昼夜节律表达特征的哺乳动物同源基因（Dec1和Dec2）的存在表明，哺乳动物时钟中也存在类似的反馈机制。
Many organisms use circadian clocks to keep temporal order and anticipate daily environmental changes. In Drosophila, the master clock gene Clock promotes the transcription of several key target genes. Two of these gene products, PER and TIM, repress CLK-CYC-mediated transcription. To recognize additional direct CLK target genes, we designed a genome-wide approach and identified clockwork orange (cwo) as a new core clock component. cwo encodes a transcriptional repressor that synergizes with PER and inhibits CLK-mediated activation. Consistent with this function, the mRNA profiles of CLK direct target genes in cwo mutant flies manifest high trough values and low amplitude oscillations. Because behavioral rhythmicity fails to persist in constant darkness ( DD) with little or no effect on average mRNA levels in flies lacking cwo, transcriptional oscillation amplitude appears to be linked to rhythmicity. Moreover, the mutant flies are long period, consistent with the late repression indicated by the RNA profiles. These findings suggest that CWO acts preferentially in the late night to help terminate CLK-CYC-mediated transcription of direct target genes including cwo itself. The presence of mammalian homologs with circadian expression features (Dec1 and Dec2) suggests that a similar feedback mechanism exists in mammalian clocks.