Nonsense-Mediated RNA Decay Influences Human Embryonic Stem Cell Fate

Nonsense-mediated RNA decay (NMD) is a highly conserved pathway that selectively degrades specific subsets of RNA transcripts. Here, we provide evidence that NMD regulates early human developmental cell fate. We found that NMD factors tend to be expressed at higher levels in human pluripotent cells than in differentiated cells, raising the possibility that NMD must be downregulated to permit differentiation. Loss- and gain-of-function experiments in human embryonic stem cells (hESCs) demonstrated that, indeed, NMD downregulation is essential for efficient generation of definitive endoderm. RNA-seq analysis identified NMD target transcripts induced when NMD is suppressed in hESCs, including many encoding signaling components. This led us to test the role of TGF-β and BMP signaling, which we found NMD acts through to influence definitive endoderm versus mesoderm fate. Our results suggest that selective RNA decay is critical for specifying the developmental fate of specific human embryonic cell lineages. •The NMD RNA degradation pathway is highly active in pluripotent cells•RNA-seq analysis identifies mRNA targets of NMD in human embryonic stem cells•NMD degrades mRNAs encoding TGF-β/BMP, WNT, and FGF signaling components•NMD acts through signaling pathways to influence endoderm versus mesoderm cell fate In this report, Wilkinson and colleagues show that the conserved RNA degradation pathway—nonsense-mediated RNA decay (NMD)—is highly active in human embryonic stem cells (hESCs). They demonstrate that NMD degrades mRNAs encoding components of signaling pathways critical for primary germ-layer differentiation. hESC differentiation modulates NMD magnitude, which strongly influences mesoderm versus definitive endoderm cell fate.