Format

Send to

Choose Destination
Cell Stem Cell. 2019 Sep 27. pii: S1934-5909(19)30385-6. doi: 10.1016/j.stem.2019.08.018. [Epub ahead of print]

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

Author information

1
Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; Harvard Stem Cell Institute, 1350 Massachusetts Avenue, Cambridge, MA 02138, USA.
2
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA; Stem Cell Program, University of California San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
3
Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
4
Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
5
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
6
Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; Harvard Stem Cell Institute, 1350 Massachusetts Avenue, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
7
Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
8
Harvard Stem Cell Institute, 1350 Massachusetts Avenue, Cambridge, MA 02138, USA; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
9
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA; Stem Cell Program, University of California San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California at San Diego, La Jolla, CA 92093, USA. Electronic address: geneyeo@ucsd.edu.
10
Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; Harvard Stem Cell Institute, 1350 Massachusetts Avenue, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: khochedlinger@mgh.harvard.edu.

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.

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

PMID:
31588046
DOI:
10.1016/j.stem.2019.08.018

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center