Transcription of the Geminin gene is regulated by a negative-feedback loop.
Transcription of the Geminin gene is regulated by a negative-feedback loop.
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DOI：
10.1091/mbc.e13-09-0534
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发表时间：
2014-04
影响因子：
3.3
通讯作者：
Takihara Y
中科院分区：
文献类型：
--
作者：
Ohno Y;Saeki K;Yasunaga S;Kurogi T;Suzuki-Takedachi K;Shirai M;Mihara K;Yoshida K;Voncken JW;Ohtsubo M;Takihara Y
Geminin转录受E2 Fs调控，通过抑制染色质重塑负调控Geminin。因此，通过染色质构型的负反馈环来调节Geminin转录。稳态调节的Geminin可能有助于DNA复制和转录的偶联调节。Geminin在调节发育和干细胞中的细胞增殖和分化中发挥重要作用。有趣的是，Geminin的下调诱导由E2 F调节的基因转录，表明Geminin参与E2 F介导的转录活性的调节。由于Geminin基因的转录是通过位于第一内含子的E2 F-反应区（E2 F-R）来调节的，我们首先使用报告载体来研究Geminin对E2 F介导的转录调节的影响。我们发现，Geminin转染抑制E2 F1和E2 F2介导的转录激活，并温和地抑制这种活性与E2 F5，6和7的协同作用，这表明Geminin构成了一个负反馈环的Geminin启动子。令人感兴趣的是，Geminin还抑制核酸酶可及性、组蛋白H3的乙酰化和组蛋白H3在赖氨酸4处的三甲基化，这是由E2 F1过表达诱导的，并且增强了E2 F-R中组蛋白H3在赖氨酸27处的三甲基化和组蛋白H2 A在赖氨酸119处的单泛素化。然而，Geminin 5EQ，不与Brahma或Brg 1相互作用，不抑制核酸酶消化或转录的可及性，但具有总体显性负效应。这些结果表明，E2 F介导的激活Geminin转录负调控Geminin通过抑制染色质重塑。
Geminin transcription, regulated by E2Fs, is negatively regulated by Geminin through the inhibition of chromatin remodeling. Geminin transcription is thus regulated by a negative-feedback loop through the chromatin configuration. Homeostatically regulated Geminin may help couple regulation of DNA replication and transcription. Geminin performs a central function in regulating cellular proliferation and differentiation in development and also in stem cells. Of interest, down-regulation of Geminin induces gene transcription regulated by E2F, indicating that Geminin is involved in regulation of E2F-mediated transcriptional activity. Because transcription of the Geminin gene is reportedly regulated via an E2F-responsive region (E2F-R) located in the first intron, we first used a reporter vector to examine the effect of Geminin on E2F-mediated transcriptional regulation. We found that Geminin transfection suppressed E2F1- and E2F2-mediated transcriptional activation and also mildly suppressed such activity in synergy with E2F5, 6, and 7, suggesting that Geminin constitutes a negative-feedback loop for the Geminin promoter. Of interest, Geminin also suppressed nuclease accessibility, acetylation of histone H3, and trimethylation of histone H3 at lysine 4, which were induced by E2F1 overexpression, and enhanced trimethylation of histone H3 at lysine 27 and monoubiquitination of histone H2A at lysine 119 in E2F-R. However, Geminin5EQ, which does not interact with Brahma or Brg1, did not suppress accessibility to nuclease digestion or transcription but had an overall dominant-negative effect. These findings suggest that E2F-mediated activation of Geminin transcription is negatively regulated by Geminin through the inhibition of chromatin remodeling.