Gene Model 129 ( Gm129) Encodes a Novel Transcriptional Repressor That Modulates Circadian Gene Expression*
Gene Model 129 ( Gm129) Encodes a Novel Transcriptional Repressor That Modulates Circadian Gene Expression*
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DOI：
10.1074/jbc.m113.534651
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发表时间：
2014-02-21
影响因子：
4.8
通讯作者：
Ye, Rui
中科院分区：
文献类型：
--
作者：
Annayev, Yunus;Adar, Sheera;Ye, Rui
背景：哺乳动物的昼夜节律基因表达是由有节律的CLOCK - BMAL1活性驱动的。
结果：Gm129与DNA上的CLOCK - BMAL1复合物结合，并抑制其转录激活活性以调节昼夜节律基因表达的时相。
结论：Gm129是一种新型的昼夜节律调节因子。
意义：Gm129的发现揭示了昼夜节律基因表达的一个新的调控成分。哺乳动物的昼夜节律生物钟是一个由反馈回路组成的分子振荡器，该反馈回路涉及转录激活因子CLOCK和BMAL1，以及抑制因子隐花色素（CRY）和周期蛋白（PER）。在此我们表明，一个直接的CLOCK - BMAL1靶基因Gm129是反馈回路的一种新型调节因子。染色质免疫沉淀（ChIP）分析显示，CLOCK - BMAL1 - CRY1复合物强烈占据Gm129的启动子区域。GM129的mRNA和蛋白质水平在小鼠肝脏中都呈现出高振幅的昼夜节律振荡，并且Gm129基因编码一种定位于细胞核的蛋白质，它直接与BMAL1相互作用并抑制CLOCK - BMAL1活性。体外和体内的蛋白质 - DNA相互作用结果表明，与CRY1一样，GM129通过与DNA上的CLOCK - BMAL1复合物结合而起到抑制因子的作用。尽管Gm129（-/-）或Cry1（-/-）Gm129（-/-）小鼠保留了稳健的昼夜节律，但与对照组相比，肝脏中Nr1d1和Dbp mRNA的峰值出现了显著的时相延迟。我们的结果表明，除了CRY和PER之外，GM129蛋白作为一种转录抑制因子通过调节CLOCK - BMAL1活性对转录反馈回路有贡献。
Background: Circadian gene expression in mammals is driven by rhythmic CLOCKBMAL1 activities. Results:Gm129 binds to the CLOCKBMAL1 complex on DNA and represses its transcriptional activator activity to regulate the circadian gene expression phase. Conclusion:Gm129 is a novel circadian clock modulator. Significance: The discovery of Gm129 reveals a new regulatory component of circadian gene expression.The mammalian circadian clock is a molecular oscillator composed of a feedback loop that involves transcriptional activators CLOCK and BMAL1, and repressors Cryptochrome (CRY) and Period (PER). Here we show that a direct CLOCKBMAL1 target gene, Gm129, is a novel regulator of the feedback loop. ChIP analysis revealed that the CLOCKBMAL1CRY1 complex strongly occupies the promoter region of Gm129. Both mRNA and protein levels of GM129 exhibit high amplitude circadian oscillations in mouse liver, and Gm129 gene encodes a nuclear-localized protein that directly interacts with BMAL1 and represses CLOCKBMAL1 activity. In vitro and in vivo protein-DNA interaction results demonstrate that, like CRY1, GM129 functions as a repressor by binding to the CLOCKBMAL1 complex on DNA. Although Gm129(-/-) or Cry1(-/-)Gm129(-/-) mice retain a robust circadian rhythm, the peaks of Nr1d1 and Dbp mRNAs in liver exhibit a significant phase delay compared with control. Our results suggest that, in addition to CRYs and PERs, the GM129 protein contributes to the transcriptional feedback loop by modulating CLOCKBMAL1 activity as a transcriptional repressor.