RNA 解旋酶 DDX6 通过调节 P 体平衡控制细胞可塑性。
The RNA Helicase DDX6 Controls Cellular Plasticity by Modulating P-Body Homeostasis.
机构信息
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.
出版信息
Cell Stem Cell. 2019 Nov 7;25(5):622-638.e13. doi: 10.1016/j.stem.2019.08.018. Epub 2019 Oct 3.
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.
转录后机制有可能影响基因表达的复杂变化，但它们在细胞命运转变中的作用在很大程度上仍未得到探索。在这里，我们表明，RNA 解旋酶 DDX6 的抑制赋予了人类和小鼠诱导多能干细胞（ESCs）一种分化抗性的“超多能”状态，这种状态很容易重新编程为类似于植入前胚胎的原始状态。我们进一步证明，DDX6 在成体祖细胞中发挥着关键作用，它以依赖于上下文的方式控制自我更新和分化之间的平衡。在机制上，DDX6 介导 P 体中靶 mRNA 的翻译抑制。DDX6 活性丧失后，P 体溶解并释放编码命运指令性转录和染色质因子的 mRNA，这些因子重新进入核糖体池。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 甲基化景观来影响细胞命运。总的来说，我们的数据在 P 体平衡、染色质组织和干细胞多能性之间建立了联系。
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