A Myc-driven self-reinforcing regulatory network maintains mouse embryonic stem cell identity.
A Myc-driven self-reinforcing regulatory network maintains mouse embryonic stem cell identity.
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DOI：
10.1038/ncomms11903
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发表时间：
2016-06-15
影响因子：
16.6
通讯作者：
Zippo A
中科院分区：
文献类型：
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作者：
Fagnocchi L;Cherubini A;Hatsuda H;Fasciani A;Mazzoleni S;Poli V;Berno V;Rossi RL;Reinbold R;Endele M;Schroeder T;Rocchigiani M;Szkarłat Ż;Oliviero S;Dalton S;Zippo A
干细胞的识别依赖于外在和内在信号的整合，这直接影响到其表观遗传状态的维持。虽然Myc转录因子在干细胞自我更新和多能性中发挥着重要作用，但它们与信号通路和表观遗传调节因子的整合仍不清楚。我们通过分析胚胎干细胞的基因表达和表观遗传模式解决了这一问题，胚胎干细胞的生长依赖于有条件的Myc活性。在这里，我们表明，Myc增强了Wnt/β-连环蛋白信号通路，该通路与转录调控网络合作，维持胚胎干细胞的自我更新。MYC的激活导致Wnt拮抗剂通过直接在这些靶点上招募PrC2而在转录水平上受到抑制。随之而来的自分泌Wnt/β-catenin信号的增强诱导内源性Myc家族成员的转录激活，进而激活Myc驱动的自我强化电路。因此，我们的数据揭示了维持ESC自我更新能力的Myc依赖的自我传播的表观遗传记忆。Myc转录因子是干细胞(SC)自我更新和多能性的主要调节因子，但它如何整合其他途径的信号尚不清楚。在这里，作者证明了Myc的激活通过PRC2介导的Wnt途径的增强在自我更新的胚胎干细胞中触发表观遗传记忆。
Stem cell identity depends on the integration of extrinsic and intrinsic signals, which directly influence the maintenance of their epigenetic state. Although Myc transcription factors play a major role in stem cell self-renewal and pluripotency, their integration with signalling pathways and epigenetic regulators remains poorly defined. We addressed this point by profiling the gene expression and epigenetic pattern in ESCs whose growth depends on conditional Myc activity. Here we show that Myc potentiates the Wnt/β-catenin signalling pathway, which cooperates with the transcriptional regulatory network in sustaining ESC self-renewal. Myc activation results in the transcriptional repression of Wnt antagonists through the direct recruitment of PRC2 on these targets. The consequent potentiation of the autocrine Wnt/β-catenin signalling induces the transcriptional activation of the endogenous Myc family members, which in turn activates a Myc-driven self-reinforcing circuit. Thus, our data unravel a Myc-dependent self-propagating epigenetic memory in the maintenance of ESC self-renewal capacity. The Myc transcription factor is a major regulator of stem cell (SC) self-renewal and pluripotency but how this integrates signals from other pathways is unclear. Here, the authors show that Myc activation triggers epigenetic memory in self renewing embryonic SCs via PRC2-mediated potentiation of the Wnt pathway.