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

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The RNA Helicase DDX6 Controls Cellular Plasticity by Modulating P-Body Homeostasis.
Cell Stem Cell ( IF 19.8 ) Pub Date : 2019-10-03 , DOI: 10.1016/j.stem.2019.08.018
Bruno Di Stefano ₁ , En-Ching Luo ₂ , Chuck Haggerty ₃ , Stefan Aigner ₂ , Jocelyn Charlton ₃ , Justin Brumbaugh ₁ , Fei Ji ₄ , Inés Rabano Jiménez ₂ , Katie J Clowers ₅ , Aaron J Huebner ₁ , Kendell Clement ₆ , Inna Lipchina ₁ , Marit A C de Kort ₁ , Anthony Anselmo ₄ , John Pulice ₁ , Mattia F M Gerli ₇ , Hongcang Gu ₆ , Steven P Gygi ₅ , Ruslan I Sadreyev ₄ , Alexander Meissner ₈ , Gene W Yeo ₂ , Konrad Hochedlinger ₉

Affiliation

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.
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.
Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, 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.
Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
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.
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.

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.

中文翻译：

RNA解旋酶DDX6通过调节P体稳态来控制细胞可塑性。

转录后机制有可能影响基因表达的复杂变化，但是它们在细胞命运转变中的作用仍未得到充分探索。在这里，我们显示，RNA解旋酶DDX6的抑制赋予人类和小鼠致敏的胚胎干细胞（ESC）具分化抵抗力的“超多能”状态，该状态很容易重新编程为类似于植入前胚胎的幼稚状态。我们进一步证明，DDX6在成年祖细胞中起着关键作用，它以上下文相关的方式控制自我更新和分化之间的平衡。从机理上讲，DDX6介导了P体内靶mRNA的翻译抑制。在DDX6活性丧失后，P体溶解并释放编码命运指示性转录和染色质因子（可重新进入核糖体库）的mRNA。这些靶标的翻译增加通过重新连接未分化细胞类型的增强子，异染色质和DNA甲基化景观而影响细胞命运。总的来说，我们的数据在P体稳态，染色质组织和干细胞效能之间建立了联系。

更新日期：2019-11-09

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