1. The RNA Helicase DDX6 Controls Cellular Plasticity by Modulating P-Body Homeostasis.
- Author
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Di Stefano B, Luo EC, Haggerty C, Aigner S, Charlton J, Brumbaugh J, Ji F, Rabano Jiménez I, Clowers KJ, Huebner AJ, Clement K, Lipchina I, de Kort MAC, Anselmo A, Pulice J, Gerli MFM, Gu H, Gygi SP, Sadreyev RI, Meissner A, Yeo GW, and Hochedlinger K
- Subjects
- Animals, Cell Line, Chromatin Assembly and Disassembly genetics, DEAD-box RNA Helicases genetics, DNA Methylation, Embryonic Stem Cells cytology, Embryonic Stem Cells metabolism, Gene Expression Regulation genetics, Gene Ontology, Homeostasis genetics, Humans, Induced Pluripotent Stem Cells cytology, Induced Pluripotent Stem Cells enzymology, Jumonji Domain-Containing Histone Demethylases genetics, Jumonji Domain-Containing Histone Demethylases metabolism, Mice, Mice, Inbred C57BL, Nanog Homeobox Protein metabolism, Organoids cytology, Organoids diagnostic imaging, Organoids metabolism, Protein Biosynthesis genetics, Proteins metabolism, Proto-Oncogene Proteins genetics, RNA, Messenger metabolism, RNA-Seq, Ribonucleoproteins genetics, Ribosomes metabolism, Cell Differentiation genetics, Cell Plasticity genetics, DEAD-box RNA Helicases metabolism, Induced Pluripotent Stem Cells metabolism, Proto-Oncogene Proteins metabolism, Ribonucleoproteins metabolism
- Abstract
Post-transcriptional mechanisms have the potential to influence complex changes in gene expression, yet their role in cell fate transitions remains largely unexplored. Here, we show that suppression of the RNA helicase DDX6 endows human and mouse primed embryonic stem cells (ESCs) with a differentiation-resistant, "hyper-pluripotent" state, which readily reprograms to a naive state resembling the preimplantation embryo. We further demonstrate that DDX6 plays a key role in adult progenitors where it controls the balance between self-renewal and differentiation in a context-dependent manner. Mechanistically, DDX6 mediates the translational suppression of target mRNAs in P-bodies. Upon loss of DDX6 activity, P-bodies dissolve and release mRNAs encoding fate-instructive transcription and chromatin factors that re-enter the ribosome pool. Increased translation of these targets impacts cell fate by rewiring the enhancer, heterochromatin, and DNA methylation landscapes of undifferentiated cell types. Collectively, our data establish a link between P-body homeostasis, chromatin organization, and stem cell potency., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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