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

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Haggerty,  Chuck
Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Charlton,  Jocelyn
Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Meissner,  Alexander
Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;
Harvard Stem Cell Institute, 1350 Massachusetts Avenue, Cambridge, MA 02138, USA;
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA;

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DiStefano2019.pdf
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Citation

Di Stefano, B., Luo, E.-C., Haggerty, C., Aigner, S., Charlton, J., Brumbaugh, J., et al. (2019). The RNA Helicase DDX6 Controls Cellular Plasticity by Modulating P-Body Homeostasis. Cell Stem Cell, 25(5): e13, pp. 622-638. doi:10.1016/j.stem.2019.08.018.


Cite as: http://hdl.handle.net/21.11116/0000-0005-7950-9
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.