Genome-wide expression analysis of mouse liver reveals CLOCK-regulated circadian output genes
Genome-wide expression analysis of mouse liver reveals CLOCK-regulated circadian output genes
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DOI：
10.1074/jbc.m304564200
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发表时间：
2003-10-17
影响因子：
4.8
通讯作者：
Ishida, N
中科院分区：
文献类型：
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作者：
Oishi, K;Miyazaki, K;Ishida, N
CLOCK是哺乳动物视交叉上核中的中心昼夜节律振荡器的基于转录/抑制的负反馈回路的正性组分。为了检测外周组织中的时钟调节的昼夜节律转录，我们使用从时钟突变小鼠中分离的肝脏RNA进行了微阵列分析。我们还比较了隐花色素（Cry 1和Cry 2）双敲除小鼠的表达谱。我们确定了100多个基因，这些基因从白天到晚上波动，并且在Clock突变小鼠中表达水平降低。在Cry缺陷小鼠中，大多数CLOCK调节基因的表达水平升高到正常振荡的上限。大多数筛选的基因在5 '侧翼区具有CLOCK/BMAL 1结合位点（E box）。我们发现，CLOCK绝对与一种类型的肝脏基因（如DBP，TEF和Usp 2）的昼夜节律转录有关，并部分与另一种基因（如mPer 1，mPer 2，mDec 1，Nocturning，P450氧化还原酶和FKBP 51）有关，因为后者在突变小鼠中是阻尼的，但仍保持节奏。我们的研究结果表明，CLOCK和CRY蛋白参与了小鼠肝脏中许多昼夜节律输出基因的转录调控。除了作为驱动昼夜节律振荡器的负反馈回路的核心成分外，CLOCK似乎还参与各种生理功能，如细胞周期，脂质代谢，免疫功能和外周组织中的蛋白质水解。
CLOCK is a positive component of a transcription/ translation-based negative feedback loop of the central circadian oscillator in the suprachiasmatic nucleus in mammals. To examine CLOCK-regulated circadian transcription in peripheral tissues, we performed microarray analyses using liver RNA isolated from Clock mutant mice. We also compared expression profiles with those of Cryptochromes (Cry1 and Cry2) double knockout mice. We identified more than 100 genes that fluctuated from day to night and of which expression levels were decreased in Clock mutant mice. In Cry-deficient mice, the expression levels of most CLOCK-regulated genes were elevated to the upper range of normal oscillation. Most of the screened genes had a CLOCK/BMAL1 binding site (E box) in the 5'-flanking region. We found that CLOCK was absolutely concerned with the circadian transcription of one type of liver genes ( such as DBP, TEF, and Usp2) and partially with another ( such as mPer1, mPer2, mDec1, Nocturnin, P450 oxidoreductase, and FKBP51) because the latter were damped but remained rhythmic in the mutant mice. Our results showed that CLOCK and CRY proteins are involved in the transcriptional regulation of many circadian output genes in the mouse liver. In addition to being a core component of the negative feedback loop that drives the circadian oscillator, CLOCK also appears to be involved in various physiological functions such as cell cycle, lipid metabolism, immune functions, and proteolysis in peripheral tissues.