Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Stem Cells. 2013 Jun;31(6):1107-20. doi: 10.1002/stem.1365.
In pluripotent stem cells, bivalent domains mark the promoters of developmentally regulated loci. Histones in these chromatin regions contain coincident epigenetic modifications of gene activation and repression. How these marks are transmitted to maintain the pluripotent state in daughter progeny remains poorly understood. Our study demonstrates that Oct4 post-translational modifications (PTMs) form a positive feedback loop, which promotes Akt activation and interaction with Hmgb2 and the SET complex. This preserves H3K27me3 modifications in daughter progeny and maintains the pluripotent gene expression signature in murine embryonic stem cells. However, if Oct4 is not phosphorylated, a negative feedback loop is formed that inactivates Akt and initiates the DNA damage response. Oct4 sumoylation then is required for G1/S progression and transmission of the repressive H3K27me3 mark. Therefore, PTMs regulate the ability of Oct4 to direct the spatio-temporal formation of activating and repressing complexes to orchestrate chromatin plasticity and pluripotency. Our work highlights a previously unappreciated role for Oct4 PTM-dependent interactions in maintaining restrained Akt signaling and promoting a primitive epigenetic state.
在多能干细胞中，双价结构域标记了发育调控基因座的启动子。这些染色质区域中的组蛋白包含基因激活和抑制的同时发生的表观遗传修饰。这些标记如何传递以在子后代中维持多能状态仍知之甚少。我们的研究表明，Oct4 的翻译后修饰 (PTM) 形成正反馈回路，促进 Akt 的激活，并与 Hmgb2 和 SET 复合物相互作用。这在子后代中保留了 H3K27me3 修饰，并维持了小鼠胚胎干细胞中的多能基因表达特征。然而，如果 Oct4 没有被磷酸化，则会形成负反馈回路，失活 Akt 并启动 DNA 损伤反应。然后，需要 Oct4 的 SUMO 化来促进 G1/S 进程和抑制性 H3K27me3 标记的传递。因此，PTM 调节 Oct4 指导激活和抑制复合物时空形成的能力，以协调染色质可塑性和多能性。我们的工作强调了 Oct4 PTM 依赖性相互作用在维持受限的 Akt 信号传导和促进原始表观遗传状态方面的先前未被认识的作用。
