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

• Published in: Cell stem cell Vol. 25; no. 5; pp. 622 - 638.e13
• Main Authors: Di Stefano, Bruno, Luo, En-Ching, Haggerty, Chuck, Aigner, Stefan, Charlton, Jocelyn, Brumbaugh, Justin, Ji, Fei, Rabano Jiménez, Inés, Clowers, Katie J., Huebner, Aaron J., Clement, Kendell, Lipchina, Inna, de Kort, Marit A.C., Anselmo, Anthony, Pulice, John, Gerli, Mattia F.M., Gu, Hongcang, Gygi, Steven P., Sadreyev, Ruslan I., Meissner, Alexander, Yeo, Gene W., Hochedlinger, Konrad
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.11.2019
• Subjects: adult progenitor cells; chromatin; differentiation; embryonic stem cells; exit from pluripotency; naive pluripotency; P-body; post-transcriptional regulation; primed pluripotency; RNA helicase DDX6; self-renewal; differentiation; P-body; primed pluripotency; exit from pluripotency; embryonic stem cells; post-transcriptional regulation; naive pluripotency; chromatin; adult progenitor cells; self-renewal; RNA helicase DDX6
• ISSN: 1934-5909; 1875-9777; 1875-9777
• DOI: 10.1016/j.stem.2019.08.018

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. [Display omitted] •DDX6-depleted PSCs lose P-bodies and cannot exit pluripotency•DDX6 depletion perturbs adult stem potency in a context-dependent manner•DDX6 suppresses the translation of P-body enriched TFs and chromatin regulators•P-body loss profoundly alters chromatin organization in stem cells P-bodies are cytoplasmic RNP granules whose role in stem cells remains largely elusive. Di Stefano et al. show that the disruption of P-bodies upon loss of DDX6 perturbs the self-renewal and differentiation of various stem cell populations through translational upregulation of cell fate regulators and profound rewiring of chromatin landscapes.