Widespread transcriptional pausing and elongation control at enhancers.
Widespread transcriptional pausing and elongation control at enhancers.
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DOI：
10.1101/gad.309351.117
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发表时间：
2018-01-01
影响因子：
10.5
通讯作者：
Adelman K
中科院分区：
文献类型：
--
作者：
Henriques T;Scruggs BS;Inouye MO;Muse GW;Williams LH;Burkholder AB;Lavender CA;Fargo DC;Adelman K
在这项研究中，Henriques 等人。证明转录是果蝇和哺乳动物细胞中增强子的几乎普遍特征，并且新生 RNA 测序策略对于识别增强子和超级增强子是最佳的。他们的发现提供了对超级增强剂独特特征的见解，超级增强剂通过快速暂停释放刺激高水平基因表达；有趣的是，这一特性使得相关基因能够抵抗稳定暂停 RNAPII 的因子的丢失。基因远端增强子的调节对于细胞类型特异性和条件特异性的基因表达模式至关重要。因此，为了了解给定细胞类型或组织中基因活性的基础，我们必须确定增强子的精确位置并在功能上表征它们的行为。在这里，我们证明转录是果蝇和哺乳动物细胞中增强子的几乎普遍特征，并且新生的 RNA 测序策略对于识别增强子和超级增强子是最佳的。我们剖析了控制增强子转录的机制，发现与蛋白质编码基因的转录有显着的相似之处。我们证明 RNA 聚合酶 II (RNAPII) 在增强子处经历受调节的暂停和释放。然而，与mRNA基因相比，增强子处的RNAPII稳定性较差，更容易提前终止。此外，我们发现增强子处的组蛋白 H3 Lys4 (H3K4) 甲基化水平与转录活性相对应，因此高活性增强子显示出 H3K4 三甲基化，而不是被认为是增强子标志的 H3K4 单甲基化。最后，我们的工作提供了对超级增强剂独特特征的见解，超级增强剂通过快速暂停释放刺激高水平基因表达；有趣的是，这一特性使得相关基因能够抵抗稳定暂停 RNAPII 的因子的丢失。
In this study, Henriques et al. demonstrate that transcription is a nearly universal feature of enhancers in Drosophila and mammalian cells and that nascent RNA sequencing strategies are optimal for identification of both enhancers and superenhancers. Their findings provide insights into the unique characteristics of superenhancers, which stimulate high-level gene expression through rapid pause release; interestingly, this property renders associated genes resistant to loss of factors that stabilize paused RNAPII. Regulation by gene-distal enhancers is critical for cell type-specific and condition-specific patterns of gene expression. Thus, to understand the basis of gene activity in a given cell type or tissue, we must identify the precise locations of enhancers and functionally characterize their behaviors. Here, we demonstrate that transcription is a nearly universal feature of enhancers in Drosophila and mammalian cells and that nascent RNA sequencing strategies are optimal for identification of both enhancers and superenhancers. We dissect the mechanisms governing enhancer transcription and discover remarkable similarities to transcription at protein-coding genes. We show that RNA polymerase II (RNAPII) undergoes regulated pausing and release at enhancers. However, as compared with mRNA genes, RNAPII at enhancers is less stable and more prone to early termination. Furthermore, we found that the level of histone H3 Lys4 (H3K4) methylation at enhancers corresponds to transcriptional activity such that highly active enhancers display H3K4 trimethylation rather than the H3K4 monomethylation considered a hallmark of enhancers. Finally, our work provides insights into the unique characteristics of superenhancers, which stimulate high-level gene expression through rapid pause release; interestingly, this property renders associated genes resistant to the loss of factors that stabilize paused RNAPII.
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