Comprehensive analysis of promoter-proximal RNA polymerase II pausing across mammalian cell types.
Comprehensive analysis of promoter-proximal RNA polymerase II pausing across mammalian cell types.
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DOI：
10.1186/s13059-016-0984-2
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发表时间：
2016-06-03
期刊：
影响因子：
12.3
通讯作者：
Pu WT
中科院分区：
文献类型：
--
作者：
Day DS;Zhang B;Stevens SM;Ferrari F;Larschan EN;Park PJ;Pu WT
对于许多基因，RNA聚合酶II在过渡到生产性延伸之前稳定地暂停。虽然聚合酶II暂停已被证明是一种调节转录激活的机制，在何种程度上参与控制哺乳动物基因表达及其与染色质结构的关系仍然知之甚少。在这里，我们分析了85 RNA聚合酶II染色质免疫沉淀（ChIP）测序实验从35个不同的小鼠和人类样本，以及相关的全基因组数据集，以获得新的见解聚合酶II暂停和基因调控之间的关系。在细胞和组织类型中，暂停基因（暂停指数> 2）包含约60%的表达基因，并且重复地与特定的生物学功能相关。暂停的基因也具有较低的细胞间表达变异性。增加暂停对基因表达水平具有非线性影响，中度暂停的基因比其他暂停的基因表达更高。最高的基因表达水平往往是通过高聚合酶II启动驱动的新型暂停释放机制实现的。在检查细胞外信号影响的三个数据集中，对刺激有反应的基因平均暂停指数略低于无反应基因，快速基因激活与条件性暂停释放有关。染色质结构和转录起始位点附近的局部序列组成都影响暂停，哺乳动物和果蝇之间具有不同的特征。最值得注意的是，在哺乳动物中，暂停与启动子处的组蛋白H2A.Z占用正相关。我们的结果为RNA聚合酶II暂停在哺乳动物基因调节和染色质结构中的贡献提供了新的见解。本文的在线版本（doi：10.1186/s13059-016-0984-2）包含补充材料，可供授权用户使用。
For many genes, RNA polymerase II stably pauses before transitioning to productive elongation. Although polymerase II pausing has been shown to be a mechanism for regulating transcriptional activation, the extent to which it is involved in control of mammalian gene expression and its relationship to chromatin structure remain poorly understood. Here, we analyze 85 RNA polymerase II chromatin immunoprecipitation (ChIP)-sequencing experiments from 35 different murine and human samples, as well as related genome-wide datasets, to gain new insights into the relationship between polymerase II pausing and gene regulation. Across cell and tissue types, paused genes (pausing index > 2) comprise approximately 60 % of expressed genes and are repeatedly associated with specific biological functions. Paused genes also have lower cell-to-cell expression variability. Increased pausing has a non-linear effect on gene expression levels, with moderately paused genes being expressed more highly than other paused genes. The highest gene expression levels are often achieved through a novel pause-release mechanism driven by high polymerase II initiation. In three datasets examining the impact of extracellular signals, genes responsive to stimulus have slightly lower pausing index on average than non-responsive genes, and rapid gene activation is linked to conditional pause-release. Both chromatin structure and local sequence composition near the transcription start site influence pausing, with divergent features between mammals and Drosophila. Most notably, in mammals pausing is positively correlated with histone H2A.Z occupancy at promoters. Our results provide new insights into the contribution of RNA polymerase II pausing in mammalian gene regulation and chromatin structure. The online version of this article (doi:10.1186/s13059-016-0984-2) contains supplementary material, which is available to authorized users.