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.
Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Chih-Hong
CH
Lou
Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Jennifer
J
Chousal
Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Alexandra
A
Goetz
Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Eleen Y
EY
Shum
School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ 85281, USA.
David
D
Brafman
Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Xiaoyan
X
Liao
Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Sergio
S
Mora-Castilla
Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Madhuvanthi
M
Ramaiah
Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Heidi
H
Cook-Andersen
Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Louise
L
Laurent
Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: mfwilkinson@ucsd.edu.
Miles F
MF
Wilkinson
D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics*; D004475:Ectoderm / Q000166:cytology / Q000378:metabolism; D004707:Endoderm / Q000166:cytology / Q000378:metabolism*; D020869:Gene Expression Profiling; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D059365:Nonsense Mediated mRNA Decay; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D020365:RNA Helicases; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D015534:Trans-Activators; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D012333:RNA, Messenger; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D020365:RNA Helicases; C101828:UPF1 protein, human