Pausing of RNA polymerase II regulates mammalian developmental potential through control of signaling networks.
Pausing of RNA polymerase II regulates mammalian developmental potential through control of signaling networks.
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DOI：
10.1016/j.molcel.2015.02.003
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发表时间：
2015-04-16
期刊：
影响因子：
16
通讯作者：
Adelman, Karen
中科院分区：
文献类型：
--
作者：
Williams, Lucy H.;Fromm, George;Gokey, Nolan G.;Henriques, Telmo;Muse, Ginger W.;Burkholder, Adam;Fargo, David C.;Hu, Guang;Adelman, Karen
胚胎干细胞(ESCs)具有显著的多能性和自我更新能力，需要一个微调的转录电路，其中启动分化的途径和基因受到抑制，但准备对发育信号做出快速反应。为了阐明小鼠胚胎干细胞在幼稚、基态下的转录调控，我们定义了高分辨率下参与的RNA聚合酶II(POL II)的分布。我们发现POL II的启动子-近端停顿在调控细胞周期和信号转导的基因上最丰富，而不是像预期的那样在发育或二价基因上丰富。因此，去除主要的暂停诱导因子NELF不会增加谱系标记的表达，而是会导致增殖缺陷、胚胎死亡和ESC信号通路的失调。事实上，缺乏NELF的ESCs已经显著降低了成纤维细胞生长因子/ERK的活性，使它们对分化产生抵抗。因此，这项工作揭示了NELF介导的暂停在建立干细胞对发育线索的反应性方面的关键作用。
The remarkable capacity for pluripotency and self-renewal in embryonic stem cells (ESCs) requires a finely-tuned transcriptional circuitry wherein the pathways and genes that initiate differentiation are suppressed, but poised to respond rapidly to developmental signals. To elucidate transcriptional control in mouse ESCs in the naïve, ground state, we defined the distribution of engaged RNA polymerase II (Pol II) at high-resolution. We find that promoter-proximal pausing of Pol II is most enriched at genes regulating cell cycle and signal transduction, and not, as expected, at developmental or bivalent genes. Accordingly, ablation of the primary pause-inducing factor NELF does not increase expression of lineage markers, but instead causes proliferation defects, embryonic lethality and dysregulation of ESC signaling pathways. Indeed, ESCs lacking NELF have dramatically attenuated FGF/ERK activity, rendering them resistant to differentiation. This work thus uncovers a key role for NELF-mediated pausing in establishing the responsiveness of stem cells to developmental cues.
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影响因子：
23.9
作者：
Brookes, Emily;de Santiago, Ines;Hebenstreit, Daniel;Morris, Kelly J.;Carroll, Tom;Xie, Sheila Q.;Stock, Julie K.;Heidemann, Martin;Eick, Dirk;Nozaki, Naohito;Kimura, Hiroshi;Ragoussis, Jiannis;Teichmann, Sarah A.;Pombo, Ana
通讯作者：
Pombo, Ana
影响因子：
11.8
作者：
Chazaud, Claire;Yamanaka, Yojiro;Rossant, Janet
通讯作者：
Rossant, Janet
DOI：
10.1126/science.1181421
发表时间：
2010-01-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Nechaev S;Fargo DC;dos Santos G;Liu L;Gao Y;Adelman K
通讯作者：
Adelman K
影响因子：
8.8
作者：
Gaertner B;Johnston J;Chen K;Wallaschek N;Paulson A;Garruss AS;Gaudenz K;De Kumar B;Krumlauf R;Zeitlinger J
通讯作者：
Zeitlinger J
影响因子：
64.5
作者：
Levine M
通讯作者：
Levine M