System-level identification of transcriptional circuits underlying mammalian circadian clocks
System-level identification of transcriptional circuits underlying mammalian circadian clocks
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DOI：
10.1038/ng1504
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发表时间：
2005-02-01
期刊：
影响因子：
30.8
通讯作者：
Hashimoto, S
中科院分区：
文献类型：
--
作者：
Ueda, HR;Hayashi, S;Hashimoto, S
哺乳动物的生物钟由复杂整合的调节回路组成（1-5），如果没有系统动力学的准确测量和网络回路的全面识别，就很难阐明它们（6）。为了对这种转录电路的系统级理解，我们确定了16个时钟和时钟控制的基因在进化上保守的顺式元件和测量其转录动力学的全面监督的时钟控制元件。在这里，我们报告了E/E'盒，DBP/E4 BP 4结合元件（7）和RevErbA/ROR结合元件（8）在9个，7个和6个基因中的作用。我们的研究结果表明，昼夜转录电路由两个设计原则：调节E/E盒和RevErbA/ROR结合元件遵循阻遏物-前激活模式，导致延迟的转录活性，而DBP/E4 BP 4结合元件的调节遵循阻遏物-反相-激活机制，产生高幅度的转录活性。我们的分析进一步表明，E/E盒的调节是哺乳动物生物钟中的拓扑脆弱性，这一概念已在功能上使用体外表型测定系统进行了验证。
Mammalian circadian clocks consist of complexly integrated regulatory loops(1-5), making it difficult to elucidate them without both the accurate measurement of system dynamics and the comprehensive identification of network circuits(6). Toward a system-level understanding of this transcriptional circuitry, we identified clock-controlled elements on 16 clock and clock-controlled genes in a comprehensive surveillance of evolutionarily conserved cis elements and measurement of their transcriptional dynamics. Here we report the roles of E/E' boxes, DBP/E4BP4 binding elements(7) and RevErbA/ROR binding elements(8) in nine, seven and six genes, respectively. Our results indicate that circadian transcriptional circuits are governed by two design principles: regulation of E/E boxes and RevErbA/ROR binding elements follows a repressor-precedes-activator pattern, resulting in delayed transcriptional activity, whereas regulation of DBP/E4BP4 binding elements follows a repressor-antiphasic-to-activator mechanism, which generates high-amplitude transcriptional activity. Our analysis further suggests that regulation of E/E boxes is a topological vulnerability in mammalian circadian clocks, a concept that has been functionally verified using in vitro phenotype assay systems.