Role of co-repressor genomic landscapes in shaping the Notch response.
Role of co-repressor genomic landscapes in shaping the Notch response.
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DOI：
10.1371/journal.pgen.1007096
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发表时间：
2017-11
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：
Chan SKK;Cerda-Moya G;Stojnic R;Millen K;Fischer B;Fexova S;Skalska L;Gomez-Lamarca M;Pillidge Z;Russell S;Bray SJ
阻遏物经常被用来限制对信号通路的转录反应。例如，几种共抑制因子直接与dna结合蛋白CSL相互作用，并被认为在缺乏Notch活性的情况下保持靶基因沉默。然而，他们的贡献范围仍不清楚。为了在这种明确的信号通路中研究共抑制因子的活性，我们分析了果蝇中最具特征的CSL共抑制因子，无毛，以及第二个CSL相互作用抑制因子SMRTER的全基因组结合谱。正如预测的那样，在Kc细胞和翅盘中，Hairless和它的CSL dna结合伙伴之间存在显著的重叠，它们主要存在于具有活性增强子标记的染色质中。然而，尽管无毛复合物广泛存在于一些Notch调节的翼盘增强子上，但在其他地方没有检测到结合，这表明它本身并不是沉默所必需的。对目标增强剂的进一步分析证实了对无毛产品的不同要求。SMRTER与Hairless的结合明显重叠，而不是互补，许多增强子明显被这两个因子共同结合。我们的分析表明，Hairless和SMRTER门增强子分别对Notch活性和Ecdysone信号传导起作用，以确保达到适当的靶基因表达水平和时间。细胞间的通信发生在发育过程中，以及在疾病背景下，涉及少量信号通路，其中Notch通路是其中之一。一个突出的问题是这些途径如何在不同的环境下带来不同的基因反应。由于基因表达是由激活因子和抑制因子的混合物协调的，我们开始研究抑制因子在基因组中的分布是否对基因是否能够对Notch活性做出反应有重要影响。我们分析了两种抑制因子Hairless和SMRTER的结合谱，结果表明，在许多情况下，它们并不是阻止基因应答所必需的。相反，它们被部署在有限数量的基因位点上，在那里它们控制反应，帮助设定基因激活的阈值。对其功能的扰动导致有限区域内基因表达的增强，而不是基因表达的新程序。因此，它们的主要作用是限制基因在做出反应之前需要接收的信号的时间或水平。
Repressors are frequently deployed to limit the transcriptional response to signalling pathways. For example, several co-repressors interact directly with the DNA-binding protein CSL and are proposed to keep target genes silenced in the absence of Notch activity. However, the scope of their contributions remains unclear. To investigate co-repressor activity in the context of this well defined signalling pathway, we have analysed the genome-wide binding profile of the best-characterized CSL co-repressor in Drosophila, Hairless, and of a second CSL interacting repressor, SMRTER. As predicted there was significant overlap between Hairless and its CSL DNA-binding partner, both in Kc cells and in wing discs, where they were predominantly found in chromatin with active enhancer marks. However, while the Hairless complex was widely present at some Notch regulated enhancers in the wing disc, no binding was detected at others, indicating that it is not essential for silencing per se. Further analysis of target enhancers confirmed differential requirements for Hairless. SMRTER binding significantly overlapped with Hairless, rather than complementing it, and many enhancers were apparently co-bound by both factors. Our analysis indicates that the actions of Hairless and SMRTER gate enhancers to Notch activity and to Ecdysone signalling respectively, to ensure that the appropriate levels and timing of target gene expression are achieved. The communication between cells that occurs during development, as well as in disease contexts, involves a small number of signalling pathways of which the Notch pathway is one. One outstanding question is how these pathways can bring about different gene responses in different contexts. As gene expression is co-ordinated by a mixture of activators and repressors, we set out to investigate whether the distribution of repressors across the genome is important in shaping whether genes are able to respond to Notch activity. Our results from analyzing the binding profile of two repressors, Hairless and SMRTER, show that, in many cases, they are not essential for preventing a gene from responding. Instead they are deployed at a limited number of genetic loci where they gate the response, helping to set a threshold for gene activation. Perturbations to their function lead to enhanced gene expression in limited territories rather than to new programmes of gene expression. Their main role therefore is to restrict the time or levels of signal that a gene needs to receive before it will respond.
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影响因子：
3.7
作者：
Babaoğlan AB;Housden BE;Furriols M;Bray SJ
通讯作者：
Bray SJ
影响因子：
7
作者：
Koenecke, Nina;Johnston, Jeff;Zeitlinger, Julia
通讯作者：
Zeitlinger, Julia
影响因子：
2.4
作者：
Heck, Bryan W.;Zhang, Bin;Tsai, Chih-Cheng
通讯作者：
Tsai, Chih-Cheng
DOI：
10.1016/j.jgg.2016.03.002
发表时间：
2016-04-20
期刊：
Journal of genetics and genomics = Yi chuan xue bao
影响因子：
--
作者：
Jia D;Bryant J;Jevitt A;Calvin G;Deng WM
通讯作者：
Deng WM
影响因子：
11.4
作者：
Djiane, Alexandre;Krejci, Alena;Bernard, Frederic;Fexova, Silvie;Millen, Katherine;Bray, Sarah J.
通讯作者：
Bray, Sarah J.