CHIR99021 enhances Klf4 Expression through β-Catenin Signaling and miR-7a Regulation in J1 Mouse Embryonic Stem Cells.
CHIR99021 enhances Klf4 Expression through β-Catenin Signaling and miR-7a Regulation in J1 Mouse Embryonic Stem Cells.
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DOI：
10.1371/journal.pone.0150936
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Guo Z
中科院分区：
文献类型：
--
作者：
Ai Z;Shao J;Wu Y;Yu M;Du J;Shi X;Shi X;Zhang Y;Guo Z
了解胚胎干细胞（ESCs）多能性的调控机制对确保其安全临床应用具有重要意义。CHIR99021 （CHIR）诱导的Wnt/β-catenin信号通路激活促进小鼠ESCs （mESCs）的自我更新。β-catenin单独或与转录因子协同作用，激活c-Myc、Esrrb、Pou5f1和Nanog等干性因子。然而，核心多能因子kruppel样因子4（也称为GKLF或EZF）与Wnt/β-catenin信号传导之间的关系在J1 mESCs中仍然不明确。DNA微阵列分析显示，chir处理促进了维持多能性的转录因子，抑制了胚层规格标记。CHIR还促进细胞外区和质膜发育相关基因的发育，维持J1 mESCs的多能性。在chir调控基因中，Klf4此前未见报道。我们在J1 mESCs中发现了Klf4基因中一个新的顺式元件，该元件被β-catenin激活。我们确定β-catenin与这个顺式元件相互作用，在这种情况下确定Klf4是β-catenin的靶基因。此外，我们还发现了几个靶向Klf4 mRNA 3 ' -UTR的microrna，在J1 mESCs中，miR-7a被CHIR以不依赖于β-catenin的方式下调。这些数据共同表明，CHIR通过抑制miR-7a表达或典型Wnt通路激活来增强Klf4表达。
Understanding the mechanisms that regulate pluripotency of embryonic stem cells (ESCs) is important to ensure their safe clinical use. CHIR99021 (CHIR)-induced activation of Wnt/β-catenin signaling promotes self-renewal in mouse ESCs (mESCs). β-catenin functions individually or cooperates with transcription factors to activate stemness factors such as c-Myc, Esrrb, Pou5f1, and Nanog. However the relationship between the core pluripotent factor, Kruppel-like factor 4 (also known as GKLF or EZF) and Wnt/β-catenin signaling, remains ambiguous in J1 mESCs. DNA microarray analysis revealed that CHIR-treatment promoted pluripotency-maintaining transcription factors and repressed germ layer specification markers. CHIR also promoted genes related to the development of extracellular regions and the plasma membrane to maintain pluripotency of J1 mESCs. Among the CHIR-regulated genes, Klf4 has not been reported previously. We identified a novel cis element in the Klf4 gene that was activated by β-catenin in J1 mESCs. We determined that β-catenin interacted with this cis element, identifying Klf4 as a β-catenin target gene in this context. Moreover, several microRNAs that targeted the 3′-UTR of Klf4 mRNA were identified, with miR-7a being down-regulated by CHIR in a β-catenin-independent manner in J1 mESCs. These data collectively suggest that CHIR enhances Klf4 expression by repressing miR-7a expression or canonical Wnt pathway activation.
J1 小鼠 ES 细胞中 AICA 核糖核苷酸诱导的 MicroRNA 调节
影响因子：
3.7
作者：
Shi X;YongyanWu;Ai Z;Du J;Cao L;Guo Z;Zhang Y
通讯作者：
Zhang Y