Molecular characterization of the MIER2 and MIER3 transcriptional regulatory complexes

当细胞接受外部刺激或信号时，它通过改变特定基因的表达来产生反应。一些基因被激活，一些被关闭，所有这些都必须精确地协调，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是从研究细胞对成纤维细胞生长因子（FGF）的反应开始的。FGF是体内的一种自然信号，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。我在研究细胞对FGF的反应时，发现了一种新的调节基因，叫做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，它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在分子水平上是如何工作的。它就像一个中心，将其他蛋白质招募到基因组的特定位置，形成一个大型的调节复合体，控制一系列基因的表达。***在对人类基因组进行测序和分析时，鉴定出了另外两个与mier1密切相关的基因：mier2和mier3。我的实验室是世界上研究由这些基因编码的两种蛋白质MIER2和MIER3的主要实验室。到目前为止，我们的证据表明，MIER2和MIER3也可以招募其他蛋白质并形成一个复合物，该复合物的功能是控制细胞对信号作出反应所需的基因。然而，它们的作用方式不同于MIER1复合体，彼此之间也不同。***本提案的研究目标是表征MIER2和MIER3复合物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定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.