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Physiological significance of ultradian oscillatory gene expression

超电振荡基因表达的生理意义

基本信息

批准号：
21H04976
负责人：
影山龍一郎
金额：
$ 381.56万
依托单位：
Institute of Physical and Chemical Research
依托单位国家：
日本
项目类别：
Grant-in-Aid for Specially Promoted Research
财政年份：
2021
资助国家：
日本
起止时间：
2021-05-18 至 2026-03-31
项目状态：
未结题

项目摘要

神経幹細胞でHes1の発現が振動すると活性化状態に、高レベルで持続すると静止状態になる。そこで、Hes1の発現が振動する神経幹細胞、およびHes1の発現が高レベルで持続する神経幹細胞からRNAを回収し、異なる発現を示す細胞周期制御遺伝子を網羅的に探索した。その結果、サイクリン依存性キナーゼ阻害因子p21を同定した。Hes1の発現が振動するとp21の発現が抑制されて神経幹細胞の増殖が活性化されるのに対して、Hes1の発現が高レベルで持続するとp21の発現が増加して神経幹細胞の増殖が抑制されることが分かった。前者の場合は、Hes1がp21プロモーターに直接結合することでp21の発現を抑制した。後者の場合は、初めHes1はp21の発現を抑制したが、10時間後あたりからDusp7の発現を抑制してリン酸化Erkを増やすことでp21の発現を増加させた。したがって、Hes1は振動か持続かという発現動態を変えることによってp21の発現を抑制あるいは増加し、神経幹細胞の増殖を活性化あるいは抑制化することが明らかになった。次に、神経幹細胞に光遺伝学的Hes1発現誘導システムを導入し、Hes1の発現を２.5時間周期で同期振動させて経時的にRNAを回収しトランスクリプトーム解析を行った結果、Hes1と同期振動する417遺伝子を同定した。この中に、多くの細胞周期制御遺伝子が含まれていたので、今後、これらの遺伝子とHes1の発現振動との関係を明らかにする予定である。神経幹細胞ではHes1の発現振動によってプロニューラル遺伝子Neurog2の発現が振動する。その下流因子を解析したところ、徐々に蓄積してHes1の発現を抑制した。したがって、Hes1及びNeurog2のパルス数は非対称分裂開始のタイマーの役割を担うことが示唆された。

The development of Hes 1 in neural stem cells is characterized by vibration, activation, and inactivity. The development of HES1 in human stem cells, including the development of HES1 in human stem cells, and the development of HES1 in human stem cells are highly dependent on the development of RNA in human stem cells, and the development of HES1 in human stem cells, including the development of cell cycle control genes. The results, the dependency, and the resistance factor p21 are identical. In response to the increase in the activity of Hes 1 and the increase in the activity of p21 in response to the increase in the activity of Hes 1, the inhibition of Hes 1 in response to the increase in the activity of p21 in response to the increase in the activity of Hes 1 in response to the increase in the activity of p21 in response to the inhibition of Hes 1 in response to the increase in the activity of p21 in response to the increase in the activity of Hes 1 in response to the increase in the activity of p21 in response to the increase in the activity of Hes 1 in response to the increase in the activity of p21 in response to the increase in the activity of p21 in response to the inhibition of Hes 1 in response to the activity of p21 in response to the increase in the activity of p21 in response to the activity of Hes 1 in response to the increase in the activity of p21 in response to the activity of p21 in response to the activity of Hes 1 in response to the increase in response to the activity of p21 in response to the activity of p21 In the case of the former, Hes1 and p21 are directly combined to suppress the occurrence of p21. In the latter case, the occurrence of p21 was suppressed at the beginning of the period, and the occurrence of p21 was suppressed at the end of the period. The growth of stem cells is inhibited by the activation of Hes 1 and Hes 1. Next, Hes1 gene expression induced by photogenetics in human stem cells was introduced, Hes1 gene expression was detected in 2.5 time periods, and RNA gene expression was detected in 417 time periods of synchronous vibration. The relationship between these cell cycle control factors and the occurrence of Hes 1 vibration is clearly defined. Neural stem cells vibrate in response to the development of Hes1 and the development of Neurog2. The analysis and accumulation of the downflow factors in the system inhibit the occurrence of Hes1. The number of cells in Hes 1 and Neurog 2 is not equal to the number of cells in the beginning of the split.