Molecular characterization of the MIER2 and MIER3 transcriptional regulatory complexes

当细胞接受外部刺激或信号时，它会通过改变特定基因组的表达来产生反应。一些基因被激活，一些被关闭，所有这些都必须精确协调，以产生适当的反应，无论是生长，迁移还是产生激素。问题是：这是如何发生的？我回答这个问题的方法始于研究细胞如何对成纤维细胞生长因子（FGF）做出反应。FGF是体内的一种天然信号，有趣的是，它刺激成年细胞增殖，但刺激胚胎细胞停止生长，成为一种特殊的组织，如肌肉。我对细胞对FGF的反应的研究，导致了一种新的调节基因的发现，称为mier1，由这个基因产生的蛋白质，MIER1，可以控制其他基因的表达。它可以关闭细胞增殖所需的基因，也可以影响胚胎正常发育所需的基因。多年来，我们已经了解了很多关于MIER1在分子水平上如何工作的信息。它就像一个枢纽，将其他蛋白质招募到基因组中的特定位点，形成一个大型调控复合物，其功能是控制基因组的表达。 当人类基因组测序和分析时，发现了另外两个与mier1密切相关的基因：mier2和mier3。我的实验室是世界上研究这两种蛋白质的主要实验室，MIER2和MIER3，由这些基因编码。到目前为止，我们的证据表明，MIER2和MIER3还可以招募其他蛋白质，并形成一种复合物，其功能是控制细胞对信号做出反应所需的基因。然而，它们的作用方式与MIER1复合物不同，并且彼此不同。 这项研究的目标是描述MIER2和MIER3复合物的特征，并确定它们是如何工作的。通过这样做，我们将获得关于基因组的表达如何同步以产生非常特异和独特的细胞反应的基本信息。最终，这将使我们能够学习如何控制细胞行为。

When a cell receives an external stimulus or signal, it produces a response by altering the expression of specific set of genes. Some genes are activated, some are shut off, and all of this must be precisely coordinated in order to produce the proper response, whether it be to grow, to migrate or produce a hormone. The question is: how does this occur? My approach to answer this question began with studying how cells respond to fibroblast growth factor (FGF). FGF is a natural signal in the body and interestingly, it stimulates adult cells to proliferate but stimulates cells of an embryo to stop growing and become a specialized tissue, like muscle. My study of the cell's response to FGF, led to the discovery of a novel regulatory gene, called mier1, and the protein produced by this gene, MIER1, can control the expression of other genes. It can shut off genes required for a cell to proliferate and it can affect genes required for proper development of the embryo. Over the years, we have learned a lot about how MIER1 works at the molecular level. It acts like a hub to recruit other proteins to specific sites in the genome to form a large regulatory complex that functions to control expression of sets of genes. When the human genome was sequenced and analyzed, two other genes closely related to mier1 were identified: mier2 and mier3. My lab is the main lab in the world studying the two proteins, MIER2 and MIER3, encoded by these genes. Our evidence so far indicates that MIER2 and MIER3 can also recruit other proteins and form a complex that functions to control genes required for a cell to respond to a signal. However, their mode of action is distinct from the MIER1 complex and from each other. The goal of the research in this proposal is to characterize the MIER2 and MIER3 complexes and determine how they work. By doing so, we will obtain fundamental information about how the expression of groups of genes is synchronized to produce a very specific and unique cellular response. Ultimately, this would enable us to learn how to control cell behaviour.