Polycomb determines responses to smad2/3 signaling in embryonic stem cell differentiation and in reprogramming.
Polycomb determines responses to smad2/3 signaling in embryonic stem cell differentiation and in reprogramming.
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DOI：
10.1002/stem.1417
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发表时间：
2013-08
期刊：
影响因子：
5.2
通讯作者：
Kuehn, Michael R.
中科院分区：
文献类型：
--
作者：
Dahle, Oyvind;Kuehn, Michael R.
外在信号、表观遗传调节因子和内在转录因子的整合建立了多能干细胞的身份。这些成分之间的相互作用也是干细胞分化能力和分化细胞在直接重编程中重建多能状态能力的基础。多梳抑制复合物是表观遗传调节剂，在干细胞身份和分化细胞命运中发挥关键作用。 Smad2 和 Smad3 (Smad2/3) 是 Nodal/激活素/转化生长因子 (TGF)β 细胞信号通路的细胞内介质，也与干细胞多能性和分化有关。在这里，我们表明，Polycomb 对 Smad2/3 介导的信号传导做出反应，以在分化起始期间选择性调节主多能因子 Oct4 的表达，但不在自我更新多能基态下。在重编程回到基态的过程中，我们发现阻断Nodal/Activin/TGFβ信号传导所带来的重编程效率的增强也依赖于Polycomb。 Polycomb 作用对 Smad2/3 的这些上下文依赖性反应提供了一种选择性基因调控机制，可以调和该信号通路在多能性、分化和重编程中明显相互冲突的作用。
Integration of extrinsic signals, epigenetic regulators and intrinsic transcription factors establishes pluripotent stem cell identity. Interplay between these components also underlies the capacity of stem cells to undergo differentiation, and of differentiated cells to reestablish the pluripotent state in direct reprogramming. Polycomb repressive complexes are epigenetic regulators that play key roles in stem cell identity and in differentiated cell fates. Smad2 and Smad3 (Smad2/3), the intracellular mediators of the Nodal/Activin/Transforming growth factor (TGF)β cell-cell signaling pathway also are implicated in stem cell pluripotency and in differentiation. Here we show that Polycomb imposes responses to Smad2/3 mediated signaling to selectively regulate expression of the master pluripotency factor Oct4 during initiation of differentiation, but not in the self-renewing pluripotent ground state. During reprogramming back to the ground state, we find that the enhancement of reprogramming efficiency stemming from blocking Nodal/Activin/TGFβ signaling also depends on Polycomb. These context dependent responses to Smad2/3 imposed by Polycomb action provide a mechanism for selective gene regulation that can reconcile the apparently conflicting roles of this signaling pathway in pluripotency, differentiation and reprogramming.
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