Novel STAT3 Target Genes Exert Distinct Roles in the Inhibition of Mesoderm and Endoderm Differentiation in Cooperation with Nanog
Novel STAT3 Target Genes Exert Distinct Roles in the Inhibition of Mesoderm and Endoderm Differentiation in Cooperation with Nanog
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DOI：
10.1002/stem.110
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发表时间：
2009-08-01
期刊：
影响因子：
5.2
通讯作者：
Savatier, Pierre
中科院分区：
文献类型：
--
作者：
Bourillot, Pierre-Yves;Aksoy, Irene;Savatier, Pierre
白血病抑制因子 (LIF) 激活转录因子信号转导子和转录激活子 3 (STAT3)，从而通过抑制中胚层和内胚层分化来维持小鼠胚胎干细胞的多能状态。 LIF/STAT3 通路如何抑制中胚层和内胚层谱系的形成目前尚不清楚。使用激素依赖性 STAT3 并通过微阵列分析，我们鉴定了 STAT3 的 58 个靶标，其中包括 20 个未知基因。功能分析表明，所分析的 23 个 STAT3 靶基因中有 22 个有助于维持未分化状态，这一点可以通过自我更新测定中分化集落频率的增加以及敲低后早期分化标记物的伴随升高来证明。其中 14 个，包括 Dact1、Klf4、Klf5、Rgs16、Smad7、Ccrn4l、Cnnm1、Ocln、Ier3、Pim1、Cyr61 和 Sgk，也受 Nanog 调控。对谱系特异性标记的分析表明，STAT3 靶基因分为三个不同的类别，具体取决于它们抑制中胚层或内胚层分化或两者的能力。利用自我更新并且是 STAT3 和 Nanog 下游靶标的基因的鉴定揭示了小鼠胚胎干细胞中 STAT3 和 Nanog 之间功能冗余的机制。干细胞 2009;27:1760-1771
Leukemia inhibitory factor (LIF) activates the transcription factor signal transducer and activator of transcription 3 (STAT3), which results in the maintenance of mouse embryonic stem cells in the pluripotent state by inhibiting both mesodermal and endodermal differentiation. How the LIF/STAT3 pathway inhibits commitment to both mesoderm and endoderm lineages is presently unknown. Using a hormone-dependent STAT3 and with microarray analysis, we identified 58 targets of STAT3 including 20 unknown genes. Functional analysis showed that 22 among the 23 STAT3 target genes analyzed contribute to the maintenance of the undifferentiated state, as evidenced by an increase in the frequency of differentiated colonies in a self-renewal assay and a concomitant elevation of early differentiation markers upon knockdown. Fourteen of them, including Dact1, Klf4, Klf5, Rgs16, Smad7, Ccrn4l, Cnnm1, Ocln, Ier3, Pim1, Cyr61, and Sgk, were also regulated by Nanog. Analysis of lineage-specific markers showed that the STAT3 target genes fell into three distinct categories, depending on their capacity to inhibit either mesoderm or endoderm differentiation or both. The identification of genes that harness self-renewal and are downstream targets of both STAT3 and Nanog shed light on the mechanisms underlying functional redundancy between STAT3 and Nanog in mouse embryonic stem cells. STEM CELLS 2009;27:1760-1771