Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA.
Science. 2012 Oct 19;338(6105):349-54. doi: 10.1126/science.1226339. Epub 2012 Aug 30.
The mammalian circadian clock involves a transcriptional feed back loop in which CLOCK and BMAL1 activate the Period and Cryptochrome genes, which then feedback and repress their own transcription. We have interrogated the transcriptional architecture of the circadian transcriptional regulatory loop on a genome scale in mouse liver and find a stereotyped, time-dependent pattern of transcription factor binding, RNA polymerase II (RNAPII) recruitment, RNA expression, and chromatin states. We find that the circadian transcriptional cycle of the clock consists of three distinct phases: a poised state, a coordinated de novo transcriptional activation state, and a repressed state. Only 22% of messenger RNA (mRNA) cycling genes are driven by de novo transcription, suggesting that both transcriptional and posttranscriptional mechanisms underlie the mammalian circadian clock. We also find that circadian modulation of RNAPII recruitment and chromatin remodeling occurs on a genome-wide scale far greater than that seen previously by gene expression profiling.
哺乳动物的生物钟涉及一个转录反馈回路，其中 CLOCK 和 BMAL1 激活 Period 和 Cryptochrome 基因，然后这些基因反馈并抑制自身的转录。我们在小鼠肝脏中对生物钟的昼夜转录调控回路的转录结构进行了全基因组规模的研究，发现转录因子结合、RNA 聚合酶 II（RNAPII）募集、RNA 表达和染色质状态呈现出一种刻板的、随时间变化的模式。我们发现，生物钟的昼夜转录循环由三个不同的阶段组成：准备状态、协调的从头转录激活状态和受抑制状态。只有 22%的信使 RNA（mRNA）循环基因是由从头转录驱动的，这表明哺乳动物生物钟的昼夜节律既依赖于转录机制，也依赖于转录后机制。我们还发现，RNA 聚合酶 II 募集和染色质重塑的昼夜调节在全基因组范围内发生的程度远远大于以前通过基因表达谱观察到的程度。
