1. The RNA Helicase DDX6 Controls Cellular Plasticity by Modulating P-Body Homeostasis
- Author
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Kendell Clement, Chuck Haggerty, Stefan Aigner, Hongcang Gu, Alexander Meissner, Inna Lipchina, Anthony Anselmo, Steven P. Gygi, Justin Brumbaugh, Fei Ji, John L. Pulice, Mattia F. M. Gerli, Katie J. Clowers, Aaron J. Huebner, Inés Rabano Jiménez, En-Ching Luo, Ruslan I. Sadreyev, Bruno Di Stefano, Konrad Hochedlinger, Jocelyn Charlton, Marit A.C. de Kort, and Gene W. Yeo
- Subjects
Jumonji Domain-Containing Histone Demethylases ,Messenger ,RNA helicase DDX6 ,Cell Plasticity ,adult progenitor cells ,P-body ,Inbred C57BL ,self-renewal ,Regenerative Medicine ,Medical and Health Sciences ,DEAD-box RNA Helicases ,Mice ,0302 clinical medicine ,Gene expression ,Homeostasis ,primed pluripotency ,RNA-Seq ,0303 health sciences ,Cell Differentiation ,differentiation ,Nanog Homeobox Protein ,Biological Sciences ,RNA Helicase A ,Cell biology ,Chromatin ,Organoids ,Ribonucleoproteins ,DNA methylation ,Molecular Medicine ,Stem Cell Research - Nonembryonic - Non-Human ,Stem cell ,Pluripotent Stem Cells ,exit from pluripotency ,1.1 Normal biological development and functioning ,Induced Pluripotent Stem Cells ,Cell fate determination ,Biology ,Article ,Cell Line ,03 medical and health sciences ,Underpinning research ,Proto-Oncogene Proteins ,Genetics ,Animals ,Humans ,RNA, Messenger ,Post-transcriptional regulation ,Embryonic Stem Cells ,030304 developmental biology ,naive pluripotency ,Proteins ,Cell Biology ,DNA Methylation ,Stem Cell Research ,Chromatin Assembly and Disassembly ,Embryonic stem cell ,Mice, Inbred C57BL ,Gene Ontology ,Gene Expression Regulation ,Protein Biosynthesis ,RNA ,chromatin ,Generic health relevance ,Ribosomes ,030217 neurology & neurosurgery ,post-transcriptional regulation ,Developmental Biology - 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.
- Published
- 2019