Linc1557 is critical for the initiation of embryonic stem cell differentiation by directly targeting the LIF/STAT3 signaling pathway
Linc1557 is critical for the initiation of embryonic stem cell differentiation by directly targeting the LIF/STAT3 signaling pathway
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Linc1557 通过直接靶向 LIF/STAT3 信号通路，对于胚胎干细胞分化的启动至关重要
DOI：
10.1002/stem.3130
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发表时间：
2019-12-17
期刊：
影响因子：
5.2
通讯作者：
Wang, Guiying
中科院分区：
文献类型：
--
作者：
Lan, Yuanyuan;Lu, Chenqi;Wang, Guiying
胚胎干细胞（Embryonic stem cells，ESCs）具有自我更新和多向分化潜能，在发育和生物医学中发挥着重要作用。几种长链非编码RNA（lncRNA）已被报道为干细胞多能性和分化的关键调节因子。然而，lncRNA在ESC分化启动过程中的功能和调控机制尚不清楚。在这里，我们发现linc 1557在小鼠胚胎干细胞中高度表达，并且是胚胎干细胞分化起始所必需的。linc 1557的敲低增加了信号转导子和转录激活子3（STAT 3）的表达和磷酸化水平，STAT 3是白血病抑制因子（LIF）/STAT 3信号通路中的关键因子。此外，我们发现linc 1557直接与Stat 3 mRNA结合并影响其稳定性。Linc 1557基因敲减后ESCs中差异表达的转录组主要参与多细胞生物体发育和细胞分化，与Stat 3基因敲减后的差异表达相似。此外，敲低Stat 3或添加LIF/STAT 3信号传导抑制剂可挽救linc 1557敲低对小鼠ESC分化起始的抑制作用。这些发现不仅阐明了linc 1557在启动小鼠ESC分化中的关键功能，而且阐明了其直接影响Stat 3 mRNA稳定性的特定机制，这增强了对lncRNA介导的mRNA稳定性调控机制以及ESC多能性和分化中的关键信号通路的理解。
Embryonic stem cells (ESCs) have self-renewal and multi-lineage differentiation potential and perform critical functions in development and biomedicine. Several long noncoding RNAs (lncRNAs) have been reported as key regulators of stem cell pluripotency and differentiation. However, the function and regulatory mechanism of lncRNAs during the initiation of ESC differentiation remains unclear. Here, we found that linc1557 was highly expressed in mouse ESCs and required for the initiation of ESC differentiation. Knockdown of linc1557 increased the expression and phosphorylation levels of signal transducer and activator of transcription 3 (STAT3), a key factor in the leukemia inhibitory factor (LIF)/STAT3 signaling pathway. Furthermore, we found that linc1557 directly bound to Stat3 mRNA and affected its stability. The differentially expressed transcriptome after linc1557 knockdown in ESCs was involved primarily in multicellular organism development and cell differentiation as similar to that after Stat3 knockdown. Moreover, either knockdown of Stat3 or addition of a LIF/STAT3 signaling inhibitor rescued the suppressive effects of linc1557 knockdown on the initiation of mouse ESC differentiation. These findings not only elucidated the critical function of linc1557 in the initiation of mouse ESC differentiation but also clarified that its specific mechanism as directly affecting Stat3 mRNA stability, which enhanced the understanding of the lncRNA-mediated regulatory mechanism for mRNA stability and key signaling pathways in ESC pluripotency and differentiation.