Smg6/Est1 licenses embryonic stem cell differentiation via nonsense-mediated mRNA decay

Nonsense‐mediated mRNA decay (NMD) is a post‐transcriptional mechanism that targets aberrant transcripts and regulates the cellular RNA reservoir. Genetic modulation in vertebrates suggests that NMD is critical for cellular and tissue homeostasis, although the underlying mechanism remains elusive. Here, we generate knockout mice lacking Smg6/Est1, a key nuclease in NMD and a telomerase cofactor. While the complete loss of Smg6 causes mouse lethality at the blastocyst stage, inducible deletion of Smg6 is compatible with embryonic stem cell (ESC) proliferation despite the absence of telomere maintenance and functional NMD. Differentiation of Smg6‐deficient ESCs is blocked due to sustained expression of pluripotency genes, normally repressed by NMD, and forced down‐regulation of one such target, c‐Myc, relieves the differentiation block. Smg6‐null embryonic fibroblasts are viable as well, but are refractory to cellular reprograming into induced pluripotent stem cells (iPSCs). Finally, depletion of all major NMD factors compromises ESC differentiation, thus identifying NMD as a licensing factor for the switch of cell identity in the process of stem cell differentiation and somatic cell reprograming. Synopsis New genetic data show that the NMD pathway is dispensable for growth of embryonic stem cells (ESCs) but essential for differentiation and reprogramming via repression of key pluripotency genes. The RNA endonuclease Smg6 functions in telomere maintenance and nonsense‐mediated decay (NMD) in mouse ESCs and MEFs. Loss of Smg6 does not compromise the viability of ESCs and MEFs. Smg6 regulates ESC differentiation and somatic cellular reprograming via its NMD function, not telomere maintenance. Smg6 modulates ESC differentiation by controlling mRNA stability of pluripotency genes, for example, c‐Myc. The NMD pathway acts as a general RNA surveillance mechanism safeguarding the cell identity switch. Graphical Abstract New genetic data show that the NMD pathway is dispensable for growth of embryonic stem cells (ESCs) but essential for differentiation and reprogramming via repression of key pluripotency genes.