Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA.
Howard Hughes Medical Institute, Chevy Chase, MD, USA.
Am J Hum Genet. 2019 Oct 3;105(4):677-688. doi: 10.1016/j.ajhg.2019.08.003. Epub 2019 Sep 5.
Aberrant gene expression underlies many human diseases. RNA polymerase II (Pol II) pausing is a key regulatory step in transcription. Here, we mapped the locations of RNA Pol II in normal human cells and found that RNA Pol II pauses in a consistent manner across individuals and cell types. At more than 1,000 genes including MYO1E and SESN2, RNA Pol II pauses at precise nucleotide locations. Characterization of these sites shows that RNA Pol II pauses at GC-rich regions that are marked by a sequence motif. Sixty-five percent of the pause sites are cytosines. By differential allelic gene expression analysis, we showed in our samples and a population dataset from the Genotype-Tissue Expression (GTEx) consortium that genes with more paused polymerase have lower expression levels. Furthermore, mutagenesis of the pause sites led to a significant increase in promoter activities. Thus, our data uncover that RNA Pol II pauses precisely at sites with distinct sequence features that in turn regulate gene expression.
异常的基因表达是许多人类疾病的基础。RNA 聚合酶 II（Pol II）暂停是转录的关键调节步骤。在这里，我们绘制了正常人类细胞中 RNA Pol II 的位置图，发现 RNA Pol II 在个体和细胞类型之间以一致的方式暂停。在包括 MYO1E 和 SESN2 在内的 1000 多个基因中，RNA Pol II 在精确的核苷酸位置暂停。对这些位点的特征分析表明，RNA Pol II 暂停在富含 GC 的区域，这些区域被一个序列基序标记。暂停位点中有 65%是胞嘧啶。通过差异等位基因表达分析，我们在我们的样本和来自基因型-组织表达（GTEx）联盟的一个人群数据集显示，具有更多暂停聚合酶的基因表达水平较低。此外，暂停位点的诱变导致启动子活性显著增加。因此，我们的数据揭示了 RNA Pol II 精确地暂停在具有独特序列特征的位点，这些特征反过来又调节基因表达。
