Gene regulatory network structure, function and evolution

描述(由申请人提供)： 基因表达的转录调控是所有生物过程的关键。我们的大约20,000个蛋白质编码基因中的每一个都必须在正确的地点、时间和水平以及在正确的发育或生理环境下表达。因此，不适当的基因表达与无数人类疾病有关，包括先天性疾病、癌症和肥胖症。几十年来，人们对转录进行了深入的研究，从而对信使核糖核酸产生的基本生化机制有了详细的了解。然而，我们对‘系统水平’的基因调控知之甚少，即转录因子如何在复杂的基因调控网络(GRN)中共同发挥作用，以忠实地协调大量基因的表达。我们的长期目标是全面描述复杂的后生动物GRN的结构、功能和进化，以深入了解基因调控的全球机制。越来越清楚的是，教科书上对基因调控的解释过于简单化，因为许多物理的TF结合事件缺乏明显的调控结果。对此有几种解释，从技术上(例如，检测限度，将结合事件归因于错误的基因)到生物学上(例如，TF之间的冗余，条件依赖的影响)。相反，监管相互作用不一定是直接影响的结果。例如，转录因子可以级联起作用，传播功能调节。一个主要的挑战是将物理和调控相互作用结合起来，以增加我们对复杂多细胞生物体中基因调控机制的理解。许多GRN研究要么只关注物理转运蛋白相互作用，而另一些研究主要关注调节相互作用。然而，将两者结合在一起的综合GRN很少，而且如果有的话，规模相对较小。如果我们拥有高质量、大规模的物理和调控相互作用数据，以及时空和条件基因表达数据，我们可以建立越来越精确的GRN。在这里，我们将继续我们对线虫的研究，以定位和整合物理和调控GRN，这将有助于我们超越定位，在系统水平上理解复杂多细胞生物体中基因表达的调控机制。

DESCRIPTION (provided by applicant): The transcriptional regulation of gene expression is pivotal to all biological processes. Each of our ~20,000 protein-coding genes must be expressed at the right place, time and level, as well as under the right developmental or physiological circumstances. Consequently, inappropriate gene expression is implicated in a myriad of human diseases, including congenital disorders, cancer and obesity. Transcription has been studied intensively for decades, resulting in a detailed picture of the basic biochemical mechanisms of mRNA production. However, we know little about gene regulation at a 'systems level', i.e. how TFs function together in complex gene regulatory networks (GRNs) to faithfully orchestrate the expression of large sets of genes. Our long-term goal is to comprehensively characterize the structure, function and evolution of complex metazoan GRNs to gain insights into global mechanisms of gene regulation. It is becoming increasingly clear that textbook explanations of gene regulation in which a TF binds DNA in the genome and upon doing so regulates the most proximal gene are too simplistic because many physical TF binding events lack an apparent regulatory consequence. There are several explanations for this, ranging from technical (e.g. detection limits, attribution of a bindng event to the wrong gene) to biological (e.g. redundancy between TFs, condition-dependent effects). Conversely, regulatory interactions are not necessarily due to a direct effect. For instance, TFs can function in cascades to propagate functional regulation. A major challenge is to combine physical and regulatory interactions to increase our understanding of the mechanisms of gene regulation in the context of complex multicellular organisms. Many GRN studies focus either solely on physical TF interactions, whereas others focus primarily on regulatory interactions. However, integrated GRNs that combine both are scarce and, when available are relatively small in scale. If we had high-quality, large- scale physical and regulatoy interaction data, as well as spatiotemporal and conditional gene expression data, we could build increasingly precise GRNs. Here, we will continue our studies on the nematode C. elegans to map and integrate physical and regulatory GRNs, which will help us to go beyond mapping to understanding the regulatory mechanisms of gene expression at a systems level in a complex multicellular organism.