1. Nonsense-Mediated RNA Decay Influences Human Embryonic Stem Cell Fate
- Author
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Lou, Chih-Hong, Dumdie, Jennifer, Goetz, Alexandra, Shum, Eleen Y, Brafman, David, Liao, Xiaoyan, Mora-Castilla, Sergio, Ramaiah, Madhuvanthi, Cook-Andersen, Heidi, Laurent, Louise, and Wilkinson, Miles F
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Stem Cell Research ,Genetics ,Stem Cell Research - Embryonic - Human ,1.1 Normal biological development and functioning ,Generic health relevance ,Bone Morphogenetic Protein 4 ,Cell Differentiation ,Cell Line ,Cell Lineage ,Ectoderm ,Endoderm ,Gene Expression Profiling ,Human Embryonic Stem Cells ,Humans ,Mesoderm ,Nonsense Mediated mRNA Decay ,Pluripotent Stem Cells ,RNA Helicases ,RNA ,Messenger ,Sequence Analysis ,RNA ,Signal Transduction ,Trans-Activators ,Transforming Growth Factor beta ,Clinical Sciences ,Biochemistry and cell biology - Abstract
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.
- Published
- 2016