Transcriptional dynamics elicited by a short pulse of notch activation involves feed-forward regulation by E(spl)/Hes genes.
Transcriptional dynamics elicited by a short pulse of notch activation involves feed-forward regulation by E(spl)/Hes genes.
复制标题
DOI：
10.1371/journal.pgen.1003162
复制
发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Bray SJ
中科院分区：
文献类型：
--
作者：
Housden BE;Fu AQ;Krejci A;Bernard F;Fischer B;Tavaré S;Russell S;Bray SJ
Notch等信号通路的动态活性对于实现正确的发育和稳态至关重要。然而，大多数研究在信号启动后数小时或数天评估输出，一旦结果得到巩固。在这里，我们分析了转录水平的全基因组变化，Notch途径转录因子CSL（果蝇中无毛抑制因子Su（H））和RNA聚合酶II（Pol II）在短脉冲Notch刺激后的结合。共有154个基因随时间推移显示出显著的差异表达（DE），并且根据DE的时间、幅度和方向，将其表达谱分层为14个簇。E（spl）基因上调最快，Su（H）、Pol II和转录物水平在5-10分钟内增加。其他基因有更延迟的反应，其时间在很大程度上不受更长时间的Notch激活的影响。无论是Su（H）结合还是平衡的Pol II都不能完全解释谱之间的差异。相反，我们的数据表明，监管的相互作用，驱动的早期响应E（spl）bHLH基因，是必需的。提出的交叉调节关系在体内和细胞培养中得到验证，支持E（spl）bHLH/Hes的前馈抑制形成迟发反应基因的反应的观点。基于这些数据，我们提出了一个模型，其中Hes基因负责协调广泛的其他靶点的Notch反应，解释了这些关键调控因子在许多发育和疾病背景下发挥的关键功能。通过Notch通路的信号传递有助于组织成形的重要信息，并且当被滥用时，会导致疾病。细胞通过改变转录的基因来响应Notch信号。以前的大多数研究都是在信号开始很久之后的单个时间点观察基因活性的变化。通过仔细观察Notch途径激活后立即进行的定时间隔，我们已经能够跟踪所有基因转录的动态变化，并发现它们表现出不同的活性模式。例如，一些基因的活性，特别是先前表征的称为E（spl）基因的家族，很早就开始，而其他基因则显示出更延迟的上调。我们对潜在机制的研究表明，需要由早期基因驱动的交叉调节相互作用来塑造延迟反应的时机。这种前馈机制很重要，因为它解释了为什么E（spl）/Hes基因可以在Notch反应中发挥如此关键的作用，尽管许多其他基因受到信号的调节，这一发现对于理解E（spl）/Hes基因在与改变的Notch相关的疾病中的贡献是有价值的。
Dynamic activity of signaling pathways, such as Notch, is vital to achieve correct development and homeostasis. However, most studies assess output many hours or days after initiation of signaling, once the outcome has been consolidated. Here we analyze genome-wide changes in transcript levels, binding of the Notch pathway transcription factor, CSL [Suppressor of Hairless, Su(H), in Drosophila], and RNA Polymerase II (Pol II) immediately following a short pulse of Notch stimulation. A total of 154 genes showed significant differential expression (DE) over time, and their expression profiles stratified into 14 clusters based on the timing, magnitude, and direction of DE. E(spl) genes were the most rapidly upregulated, with Su(H), Pol II, and transcript levels increasing within 5–10 minutes. Other genes had a more delayed response, the timing of which was largely unaffected by more prolonged Notch activation. Neither Su(H) binding nor poised Pol II could fully explain the differences between profiles. Instead, our data indicate that regulatory interactions, driven by the early-responding E(spl)bHLH genes, are required. Proposed cross-regulatory relationships were validated in vivo and in cell culture, supporting the view that feed-forward repression by E(spl)bHLH/Hes shapes the response of late-responding genes. Based on these data, we propose a model in which Hes genes are responsible for co-ordinating the Notch response of a wide spectrum of other targets, explaining the critical functions these key regulators play in many developmental and disease contexts. Signaling via the Notch pathway conveys important information that helps to shape tissues and, when misused, contributes to diseases. Cells respond to the Notch signal by changing which genes are transcribed. Most previous studies have looked at changes in gene activity at a single time point, long after the start of signaling. By looking at carefully timed intervals immediately after Notch pathway activation, we have been able to follow the dynamic changes in transcription of all the genes and have found that they exhibit different patterns of activity. For example, activity of some genes, especially a previously characterised family called the E(spl) genes, starts very early, whereas others show more delayed upregulation. Our investigations into the underlying mechanisms reveal that cross-regulatory interactions driven by the early genes are required to shape the timing of the delayed response. This feed-forward mechanism is important because it explains why the E(spl)/Hes genes can play such a pivotal role in the Notch response, despite the fact that many other genes are regulated by the signal, a finding that will be valuable for understanding the contribution of E(spl)/Hes genes in diseases associated with altered Notch.
登录
查看更多内容
影响因子：
4.4
作者：
Elkon R;Zlotorynski E;Zeller KI;Agami R
通讯作者：
Agami R
DOI：
10.1007/978-1-4614-0899-4_15
发表时间：
2012-01-01
期刊：
NOTCH SIGNALING IN EMBRYOLOGY AND CANCER
影响因子：
--
作者：
Dang, Thao P.
通讯作者：
Dang, Thao P.
影响因子：
--
作者：
Akimov, Vyacheslav;Rigbolt, Kristoffer T. G.;Blagoev, Blagoy
通讯作者：
Blagoev, Blagoy
影响因子：
10.5
作者：
BAILEY, AM;POSAKONY, JW
通讯作者：
POSAKONY, JW
影响因子：
56.9
作者：
Hirata, H;Yoshiura, S;Kageyama, R
通讯作者：
Kageyama, R