RNA解旋酶DDX6調控細胞可塑性



本期文章:《細胞—干細胞》:Online/在線發表

美國麻省總醫院的Konrad Hochedlinger和加州大學舊金山分校的Gene W. Yeo等研究人員合作發現,RNA解旋酶DDX6通過調節P小體穩態來控制細胞可塑性。這一研究成果2019年10月3日在線發表在國際學術期刊《細胞—干細胞》上。

研究人員發現對RNA解旋酶DDX6的抑制使得人類和小鼠活化的胚胎干細胞(ESC)具有分化抗性,即“高多能”狀態,該狀態很容易重新編程為類似于植入前胚胎的初始狀態。研究人員進一步證明,DDX6在成年祖細胞中起關鍵作用,它以背景相關的方式控制自我更新與分化之間的平衡。從機理上講,DDX6介導了P小體內靶mRNA的翻譯抑制。在DDX6活性喪失后,P小體溶解并釋放編碼命運指示性轉錄和染色質因子的mRNA,從而重新進入核糖體。這些靶基因翻譯的增加通過重連未分化細胞類型的增強子、異染色質和DNA甲基化狀態而影響細胞命運??偟膩碚f,這些數據在P小體穩態、染色質組織和干細胞潛能之間建立了聯系。

據悉,轉錄后機制有可能影響基因表達的復雜變化,但是它們在細胞命運轉變中的作用仍未得到充分探索。

附:英文原文

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

Author: Bruno Di Stefano, En-Ching Luo, Chuck Haggerty, Stefan Aigner, Jocelyn Charlton, Justin Brumbaugh, Fei Ji, Inés Rabano Jiménez, Katie J. Clowers, Aaron J. Huebner, Kendell Clement, Inna Lipchina, Marit A.C. de Kort, Anthony Anselmo, John Pulice, Mattia F.M. Gerli, Hongcang Gu, Steven P. Gygi, Ruslan I. Sadreyev, Alexander Meissner, Gene W. Yeo, Konrad Hochedlinger

Issue&Volume: 3 October 2019

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.

DOI: 10.1016/j.stem.2019.08.018

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30385-6

期刊信息

Cell Stem Cell:《細胞—干細胞》,創刊于2007年。隸屬于細胞出版社,最新IF:21.464
官方網址:https://www.cell.com/cell-stem-cell/home
投稿鏈接:https://www.editorialmanager.com/cell-stem-cell/default.aspx




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