Di Stefano, B;
Luo, E-C;
Haggerty, C;
Aigner, S;
Charlton, J;
Brumbaugh, J;
Ji, F;
... Hochedlinger, K; + view all
(2019)
The RNA Helicase DDX6 Controls Cellular Plasticity by Modulating P-Body Homeostasis.
Cell Stem Cell
, 25
(5)
622-638.e13.
10.1016/j.stem.2019.08.018.
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Di Stefano et al Cell stem Cell 2019.pdf - Published Version Download (6MB) | Preview |
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.
| Type: | Article |
|---|---|
| Title: | The RNA Helicase DDX6 Controls Cellular Plasticity by Modulating P-Body Homeostasis |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.stem.2019.08.018 |
| Publisher version: | https://doi.org/10.1016/j.stem.2019.08.018 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | embryonic stem cells, adult progenitor cells, exit from pluripotency, self-renewal, differentiation, P-body, RNA helicase DDX6, post-transcriptional regulation, naive pluripotency, primed pluripotency, chromatin |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10096968 |
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