Pwp1 Is Required for the Differentiation Potential of Mouse Embryonic Stem Cells Through Regulating Stat3 Signaling
Pwp1 Is Required for the Differentiation Potential of Mouse Embryonic Stem Cells Through Regulating Stat3 Signaling
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DOI：
10.1002/stem.1876
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发表时间：
2015-03
期刊：
影响因子：
5.2
通讯作者：
Junwei Shen;Wenwen Jia;Yangyang Yu;Jie Chen;Xinkai Cao;Yanhua Du;Xiaobai Zhang;Songcheng Zhu
中科院分区：
文献类型：
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作者：
Junwei Shen;Wenwen Jia;Yangyang Yu;Jie Chen;Xinkai Cao;Yanhua Du;Xiaobai Zhang;Songcheng Zhu
白血病抑制因子/Stat 3信号传导对于维持小鼠胚胎干细胞（mESCs）的自我更新和分化潜力至关重要。然而，该通路的上游效应子尚未明确定义。在这里，我们发现周期性色氨酸蛋白1（Pwp 1），一种与组蛋白H4修饰相关的含有WD-40重复序列的蛋白质，是mESC从多能状态退出到所有谱系所必需的。Pwp 1的敲低（KD）不影响mESC增殖、自我更新或凋亡。然而，Pwp 1的KD在体外和体内均损害mESCs的分化潜能。PWP 1染色质免疫沉淀-测序结果显示，PWP 1占据的区域标记有显著水平的H4 K20 me 3。此外，Pwp 1结合到Stat 3的上游区域中的位点。Pwp 1的KD降低了Stat 3基因上游H4 K20 me 3的水平，上调了Stat 3的表达。此外，Pwp 1 KD mESCs通过抑制STAT 3的表达或抑制STAT 3的酪氨酸磷酸化来恢复其分化潜能。总之，我们的研究结果表明，Pwp 1在mESCs的分化潜能中起着重要作用。干细胞2015;33：661-673
Leukemia inhibitory factor/Stat3 signaling is critical for maintaining the self‐renewal and differentiation potential of mouse embryonic stem cells (mESCs). However, the upstream effectors of this pathway have not been clearly defined. Here, we show that periodic tryptophan protein 1 (Pwp1), a WD‐40 repeat‐containing protein associated with histone H4 modification, is required for the exit of mESCs from the pluripotent state into all lineages. Knockdown (KD) of Pwp1 does not affect mESC proliferation, self‐renewal, or apoptosis. However, KD of Pwp1 impairs the differentiation potential of mESCs both in vitro and in vivo. PWP1 chromatin immunoprecipitation‐seq results revealed that the PWP1‐occupied regions were marked with significant levels of H4K20me3. Moreover, Pwp1 binds to sites in the upstream region of Stat3. KD of Pwp1 decreases the level of H4K20me3 in the upstream region of Stat3 gene and upregulates the expression of Stat3. Furthermore, Pwp1 KD mESCs recover their differentiation potential through suppressing the expression of Stat3 or inhibiting the tyrosine phosphorylation of STAT3. Together, our results suggest that Pwp1 plays important roles in the differentiation potential of mESCs. Stem Cells 2015;33:661–673