Arginine methylation and the cell cycle

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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.