Arginine methylation and the cell cycle

精氨酸甲基化和细胞周期

• 批准号: RGPIN-2016-03672
• 负责人: Blais, Alexandre
• 金额: $ 3.21万
• 依托单位: University of Ottawa
• 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=708102
• 关键词: Arginine; methylation; cell; cycle

In cell biology, one of the most important notions to understand is condition-specific gene transcription: the idea that cells adjust the complement of genes they express based on their identity or on their needs. The way genetic information is packaged into chromatin has an immense influence on eukaryotic gene expression. It is not surprising then, that transcription factors and co-regulators work in part by precisely modulating the structure of chromatin. The covalent modification of histones, e.g. by acetylation or methylation, is a prime example of chromatin structural changes. Such histone post-translational modifications work like “marks” that can change the biophysical properties of the chromatin fiber, or serve as recognition platforms for the transcriptional machinery. My research team works to reveal the molecular mechanisms that oversee one of the most fundamental cell biology processes, the cell division cycle. In an effort to better understand the interplay between chromatin structural changes and the transcription of genes that enable cell division, we have recently focused on a relatively understudied chromatin modification: the methylation of histones on arginine side chains. In particular, we have a combination of functional genomics and biochemical approaches to characterize the role played by the enzyme Prmt5 (Protein arginine methyl-transferase 5). This enzyme is involved in symmetrically di-methylating specific arginine side chains on histones H3, H4 and H2a, but it can also methylate non-histone proteins. Among others, the results of our new experiments have revealed that Prmt5 is recruited to the promoter of hundreds of genes involved in controlling cell proliferation. Building on these preliminary findings, we want to initiate a new NSERC-funded research program that will be oriented towards understanding how Prmt5 and arginine di-methylation control cell behavior, in particular how they affect the cell division cycle. Our program revolves around three broad goals: 1-Studying the role of Prmt5 in controlling target gene expression. Are target genes induced or repressed by the action of Prmt5? Which histone arginine methylation marks depend on Prmt5 at target genes, and do relationships exist between gene activity and the various di-methyl arginine marks “written” by Prmt5? 2-Studying the mode of recruitment of Prmt5 to its target genes. Since Prmt5 does not bind to DNA directly, how is it recruited to target genes? Which transcription factors or chromatin proteins are involved? Bioinformatics and proteomics approaches will be used to identify candidates. 3-Studying non-histone targets of Prmt5 in the regulation of target gene expression. Prmt5 can methylate a number of non-histone proteins. We will explore the idea that the activity of cell cycle regulatory transcription factors is modulated by arginine methylation.

在细胞生物学中，需要理解的最重要的概念之一是条件特异性基因转录：细胞根据自己的身份或需要调整它们表达的基因的补体。遗传信息被包装成染色质的方式对真核生物的基因表达有着巨大的影响。因此，转录因子和协同调节因子在一定程度上通过精确调节染色质的结构起作用就不足为奇了。组蛋白的共价修饰，如乙酰化或甲基化，是染色质结构改变的一个主要例子。这种组蛋白翻译后修饰就像“标记”一样，可以改变染色质纤维的生物物理特性，或者作为转录机制的识别平台。