Using genome-wide data to model signalling-responsive gene regulatory networks

在胚胎发育期间，一个功能齐全的生物体的形成主要是由细胞外信号调节器和基因表达调节器来协调和控制的。胚胎发育的一个吸引人的方面是，不同细胞形成的时间总是相同的。这种同步的原因是，我们身体计划的所有信息都编码在我们的DNA中，其中包含关于我们的基因何时应该表达以及何时应该沉默的指令。此外，发育中的细胞通过信号进行交流，以同步它们的发育，并激活基因来产生蛋白质，这种蛋白质被称为转录因子，可以“读取”遗传密码。这些因素与许多其他蛋白质一起工作，以确保基因在正确的细胞和正确的时间表达。然而，染色质结构、转录因子和信号如何协同工作以适当调节基因表达尚不清楚。为了回答这个问题，我们将使用一种模拟体外正常发育的体外分化系统。我们将使用携带转基因的细胞系，这些转基因在发育的特定时间点被激活，并阐明哪些因素负责其激活以及它们如何对信号做出反应。然而，我们不会只研究一个基因，而是所有的基因，因此这个项目是湿实验室科学家和生物信息学家之间的合作。我们将使用计算生物学方法来回答在发育过程中如何控制基因表达的平衡和时间这一根本问题。

The formation of a fully functional organism during embryonic development is primarily coordinated and controlled by extra-cellular signalling modulators and regulators of gene expression. A fascinating aspect of embryonic development is that the timing of how different cells form is always the same. The reason for this synchrony is that all information for our body plan is encoded in our DNA, which contains instructions on when our genes should be expressed and when they should be silent. Moreover, developing cells communicate via signals to synchronise their development and activate genes to produce proteins, called transcription factors which can "read" the genetic code. These factors work together with many other proteins to ensure that genes are expressed in the right cell and at the right time. However, how chromatin structure, transcription factors and signals work together to properly regulate gene expression is unclear. To answer this question, we will use an in vitro differentiation system that mimics normal development in vitro. We will use cell lines that carry transgenes that are activated at defined time points in development and elucidate which factors are responsible for its activation and how they respond to signals. However, we will not just look at one gene, but at all of them and therefore the project is a collaboration between wet-lab scientists and bioinformaticians. We will use computational biology methods to answer the fundamental question of how the balance and timing of gene expression are controlled in development.