The RNA Helicase DDX6 Controls Cellular Plasticity by Modulating P-Body Homeostasis

Cell Stem Cell. 2019 Nov 7;25(5):622-638.e13. doi: 10.1016/j.stem.2019.08.018. Epub 2019 Oct 3.


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.

Keywords: P-body; RNA helicase DDX6; adult progenitor cells; chromatin; differentiation; embryonic stem cells; exit from pluripotency; naive pluripotency; post-transcriptional regulation; primed pluripotency; self-renewal.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics*
  • Cell Line
  • Cell Plasticity / genetics*
  • Chromatin Assembly and Disassembly / genetics
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism*
  • 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
  • Induced Pluripotent Stem Cells / metabolism*
  • 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
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Messenger / metabolism
  • RNA-Seq
  • Ribonucleoproteins / genetics
  • Ribonucleoproteins / metabolism*
  • Ribosomes / metabolism


  • EDC4 protein, human
  • Nanog Homeobox Protein
  • Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Ribonucleoproteins
  • Jumonji Domain-Containing Histone Demethylases
  • KDM4B protein, human
  • DDX6 protein, human
  • DEAD-box RNA Helicases