Context-specific regulation of Wnt/beta-catenin target genes

Wnt/β-catenin 靶基因的上下文特异性调控

• 批准号: BB/M001695/1
• 负责人: Stefan Hoppler
• 金额: $ 49.69万
• 依托单位: University of Aberdeen
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM001695%2F1
• 关键词: Context; specific; regulation; Wnt; beta

GENERAL RESEARCH QUESTION: One of the most important questions in biology asks how our body is built. The many cells in the embryo communicate with each other, first to arrange the general body plan and then to regulate formation of specialised cells to build our organs. These embryonic cells communicate with each other using molecular cell-to-cell signalling mechanisms. This process persists after birth when organs are repaired and tissues regenerated by continued formation of such specialised cells from resident adult stem cells. The same cell-to-cell signalling pathways as in the embryo regulate this process in the adult. Defects in signalling mechanisms consequently do not only lead to birth defects in babies but also to diseases in adults, such as cancer.SPECIFIC RESEARCH QUESTION: Wnt signalling is one of our most important molecular cell-to-cell signalling mechanisms. We already have a good understanding of the linear molecular Wnt signalling cascade, which functions to switch on or off specific genes that are needed to build specialised cells in our functional organs. However, we do not yet understand how Wnt signalling manages to find the correct genes to switch on or off in different tissues and organs. We clearly need to uncover these important mechanisms that allow Wnt signalling to function repeatedly during embryonic development and in different stem cells, while nonetheless reliably switching on or off the correct set of genes in each of these types of cells. EXPERIMENTAL SYSTEM: We have recently taken advantage of state-of-the-art molecular analysis protocols, which allow us to identify in a comprehensive manner all the genes that are switched on by Wnt signalling in a particular group of cells. We have established these methods in an accessible experimental system where we knew already about a dramatic change happening in a short time in the way Wnt signalling regulates early embryonic cells compared to slightly older cells. With these new methods we have now uncovered that Wnt signalling indeed switches on very different genes in later cells than the few we already knew about in early cells. SPECIFIC OBJECTIVES:1. Since we are now getting to know very well the set of genes switched on in later cells, we now want to carry out a proper comparison with an equally well analysed set of genes switched on in earlier cells. 2. Because we know generally which group of molecules touch switches as they are turned on or off, we now want to investigate whether different individual molecules touch different switches in different tissues, which may then allow different sets of genes to be switched on in early as compared to later cells.3. When we know the particular switches in early and in later cells and the molecules touching these switches in early and later cells, we will investigate the molecular mechanisms by which these molecules are guided to the correct switches. OUTCOMES AND BENEFITS: Our experimental model system allows us now to address these scientific questions. However, the findings from our experiments are going to be relevant not just for this experimental model system. The same Wnt signalling cascade also controls stem cells in the adult and for instance cancer cells in disease. A wide range of scientific fields will therefore benefit from our results about how different specific genes can be switched on or off by Wnt signalling in different tissues.Our experiments will also develop molecular tools and experimental approaches that will prove useful to others as they need to identify all the genes that are switched on by a certain molecular pathway in a particular group of cells; or how a specific group of molecules finds, touches and turns switches to activate these genes.

一般研究问题：生物学中最重要的问题之一询问我们的身体是如何建立的。胚胎中的许多细胞相互通信，首先是安排一般身体计划，然后调节专业细胞的形成以构建我们的器官。这些胚胎细胞使用分子细胞到细胞信号传导机制相互通信。该过程在修复器官时持续存在，并通过从居民成年干细胞中持续形成这种专门细胞而再生组织。与胚胎中相同的细胞到细胞信号通路，在成年人中调节了这一过程。因此，信号传导机制的缺陷不仅会导致婴儿的先天缺陷，还导致癌症等疾病。特定的研究问题：Wnt信号传导是我们最重要的分子细胞 - 细胞信号传导机制之一。我们已经对线性分子Wnt信号级联反应有很好的了解，该级联的功能可以打开或关闭在我们功能器官中构建专门细胞所需的特定基因。但是，我们尚不了解Wnt信号如何设法找到在不同组织和器官中打开或关闭的正确基因。我们显然需要揭示这些重要的机制，这些机制使Wnt信号在胚胎发育和不同的干细胞中反复起作用，而在每种类型的细胞中，都可以可靠地打开或关闭正确的基因集。实验系统：我们最近利用了最先进的分子分析方案，这使我们能够全面识别所有由特定细胞中Wnt信号打开的所有基因。我们已经在一个可访问的实验系统中建立了这些方法，在该系统中，我们已经知道在短时间内发生急剧变化的方式，与较老的细胞相比，Wnt信号调节早期胚胎细胞。通过这些新方法，我们现在发现了Wnt信号确实与早期细胞中已经知道的少数细胞中的基因相比，在后来的细胞中确实开了非常不同的基因。特定目标：1。由于我们现在已经非常了解后来的细胞中开启的基因集，因此我们现在希望与同样分析的基因集合中的一组在早期细胞中打开。 2。因为我们一般都知道在打开或关闭哪个分子触摸开关时，我们现在想研究不同组织中不同的单个分子是否接触不同的开关，然后与后来的细胞相比，这可能会允许早期开启不同的基因。3。当我们知道早期和后期细胞中的特定开关以及在早期和更晚细胞中接触这些开关的分子时，我们将研究这些分子被引导到正确开关的分子机制。结果和好处：我们的实验模型系统使我们现在可以解决这些科学问题。但是，我们实验的发现不仅与此实验模型系统有关。相同的Wnt信号传导级联也控制成人的干细胞，例如疾病中的癌细胞。因此，在不同组织中Wnt信号传导如何打开或关闭不同的特定基因的结果。我们的实验还将开发出分子工具和实验方法，因为它们对他人有用，因为他们需要识别所有通过特定细胞中特定细胞中某个分子途径开启的所有基因，因此，各种科学领域将受益。或特定分子如何找到，触摸和转弯开关以激活这些基因。

项目成果

Mechanical oscillations orchestrate axial patterning through Wnt activation in Hydra.

• DOI: 10.1126/sciadv.abj6897
• 发表时间: 2021-12-10
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Ferenc J;Papasaikas P;Ferralli J;Nakamura Y;Smallwood S;Tsiairis CD
• 通讯作者: Tsiairis CD

Genome-wide transcriptomics analysis identifies sox7 and sox18 as specifically regulated by gata4 in cardiomyogenesis.

• DOI: 10.1016/j.ydbio.2017.11.017
• 发表时间: 2018-02-01
• 期刊: Developmental biology
• 影响因子: 2.7
• 作者: Afouda BA;Lynch AT;de Paiva Alves E;Hoppler S
• 通讯作者: Hoppler S

A mathematical modelling portrait of Wnt signalling in early vertebrate embryogenesis

早期脊椎动物胚胎发生中 Wnt 信号传导的数学模型

• DOI: 10.48550/arxiv.2203.00779
• 发表时间: 2022
• 作者: Giuraniuc C

Genome-wide transcriptomics analysis of genes regulated by GATA4, 5 and 6 during cardiomyogenesis in Xenopus laevis.

• DOI: 10.1016/j.dib.2018.01.005
• 发表时间: 2018-04
• 期刊: Data in brief
• 影响因子: 1.2
• 作者: Afouda BA;Lynch AT;de Paiva Alves E;Hoppler S
• 通讯作者: Hoppler S

Genome-wide analysis of canonical Wnt target gene regulation in Xenopus tropicalis challenges ß-catenin paradigm.

热带非洲爪蟾典型 Wnt 靶基因调控的全基因组分析挑战了连环蛋白范式。

• 发表时间: 2017
• 作者: []