Myc基因缺失诱导出一种模拟滞育的多能性休眠状态。

Myc Depletion Induces a Pluripotent Dormant State Mimicking Diapause.

作者信息

Scognamiglio Roberta, Cabezas-Wallscheid Nina, Thier Marc Christian, Altamura Sandro, Reyes Alejandro, Prendergast Áine M, Baumgärtner Daniel, Carnevalli Larissa S, Atzberger Ann, Haas Simon, von Paleske Lisa, Boroviak Thorsten, Wörsdörfer Philipp, Essers Marieke A G, Kloz Ulrich, Eisenman Robert N, Edenhofer Frank, Bertone Paul, Huber Wolfgang, van der Hoeven Franciscus, Smith Austin, Trumpp Andreas

机构信息

Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.

Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany.

出版信息

Cell. 2016 Feb 11;164(4):668-80. doi: 10.1016/j.cell.2015.12.033.

Abstract

Mouse embryonic stem cells (ESCs) are maintained in a naive ground state of pluripotency in the presence of MEK and GSK3 inhibitors. Here, we show that ground-state ESCs express low Myc levels. Deletion of both c-myc and N-myc (dKO) or pharmacological inhibition of Myc activity strongly decreases transcription, splicing, and protein synthesis, leading to proliferation arrest. This process is reversible and occurs without affecting pluripotency, suggesting that Myc-depleted stem cells enter a state of dormancy similar to embryonic diapause. Indeed, c-Myc is depleted in diapaused blastocysts, and the differential expression signatures of dKO ESCs and diapaused epiblasts are remarkably similar. Following Myc inhibition, pre-implantation blastocysts enter biosynthetic dormancy but can progress through their normal developmental program after transfer into pseudo-pregnant recipients. Our study shows that Myc controls the biosynthetic machinery of stem cells without affecting their potency, thus regulating their entry and exit from the dormant state.

摘要

小鼠胚胎干细胞(ESCs)在MEK和GSK3抑制剂存在的情况下维持在多能性的原始基态。在此,我们表明基态ESCs表达低水平的Myc。c-myc和N-myc双缺失(dKO)或Myc活性的药理学抑制会强烈降低转录、剪接和蛋白质合成,导致增殖停滞。这个过程是可逆的,并且在不影响多能性的情况下发生,这表明Myc缺失的干细胞进入了类似于胚胎滞育的休眠状态。事实上,在滞育的囊胚中c-Myc会减少,并且dKO ESCs和滞育上胚层的差异表达特征非常相似。Myc抑制后,植入前的囊胚进入生物合成休眠状态,但在转移到假孕受体后可以通过其正常发育程序。我们的研究表明,Myc控制干细胞的生物合成机制而不影响其潜能,从而调节它们进入和退出休眠状态。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da57/4752822/cf28cef6a182/fx1.jpg

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