Molecular characterization of the MIER2 and MIER3 transcriptional regulatory complexes

MIER2 和 MIER3 转录调控复合物的分子表征

• 批准号: RGPIN-2018-04383
• 负责人: Gillespie, Laura
• 金额: $ 2.33万
• 依托单位: Memorial University of Newfoundland
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=712958
• 关键词: Molecular; characterization; MIER2; MIER3; transcriptional

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.

当细胞接收到外部刺激或信号时，它会通过改变特定基因组的表达来产生反应。有些基因被激活，有些基因被关闭，所有这些都必须精确协调才能产生适当的反应，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如何响应成纤维细胞生长因子（FGF）开始。 FGF 是体内的一种自然信号，有趣的是，它会刺激成体细胞增殖，但会刺激胚胎细胞停止生长并成为特殊组织，如肌肉。我对细胞对 FGF 反应的研究发现了一种新的调节基因，称为 mier1，而该基因产生的蛋白质 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，并可以影响胚胎正常发育所需的基因。多年来，我们对 MIER1 在分子水平上的工作原理有了很多了解。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体，其功能是控制基因组的表达。 当对人类基因组进行测序和分析时，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 还可以招募其他蛋白质并形成复合物，该复合物的功能是控制细胞响应信号所需的基因。然而，它们的作用模式与 MIER1 复合物不同，并且彼此不同。 本提案的研究目标是表征 MIER2 和 MIER3 复合体并确定它们的工作原理。通过这样做，我们将获得有关基因组的表达如何同步以产生非常具体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。