PDF(Pubmed)
Abstract：
Notch proteins undergo ligand-induced proteolysis to release a nuclear effector that influences a wide range of cellular processes by regulating transcription. Despite years of study, however, how Notch induces the transcription of its target genes remains unclear. Here, we comprehensively examined the response to human Notch1 across a time course of activation using genomic assays of nascent RNA and chromatin accessibility. These data revealed that Notch induces target gene transcription primarily by releasing paused RNA polymerase II (RNAPII), in contrast to prevailing models suggesting that Notch acts by promoting chromatin accessibility. Indeed, we found that open chromatin is established at Notch-responsive regulatory elements prior to Notch signaling, through SWI/SNF-mediated remodeling. Notch activation, however, elicited no further chromatin opening at these loci. Together, these studies reveal that the nuclear response to Notch signaling is dictated by the pre-existing chromatin state and RNAPII distribution at time of signal activation.
摘要：
Notch蛋白经历配体诱导的蛋白水解以释放通过调节转录影响广泛的细胞过程的核效应物。尽管经过多年的研究,然而,Notch如何诱导其靶基因的转录仍不清楚。这里,我们使用新生RNA和染色质可及性的基因组测定，全面检查了人类Notch1在激活过程中的反应。这些数据表明，Notch主要通过释放暂停的RNA聚合酶II（RNAPII）诱导靶基因转录，与流行的模型相反，Notch通过促进染色质可及性起作用。的确,我们发现开放染色质是在Notch信号传导之前在Notch反应调节元件上建立的，通过SWI/SNF介导的重塑。缺口激活,然而,在这些基因座处没有引起进一步的染色质开放。一起,这些研究表明,对Notch信号传导的核反应是由信号激活时预先存在的染色质状态和RNAPII分布决定的.
