Wednesday, April 2, 2025
4/2/2025
Protein arginine methylation in transcription and RNA metabolism - Project Summary/Abstract: Protein arginine methylation is an abundant and evolutionarily conserved post-translational modification (PTM) found in all eukaryotes. This process is vital for maintaining proper cellular function and normal development. However, aberrations in protein arginine methylation can lead to a variety of human diseases, such as neurodevelopmental disorders and cancer. Our long-term goal is to elucidate the molecular mechanism underlying the impact of arginine methylation in gene expression and define how this regulatory process contributes to human biology and disease. We've been pioneering this research, making significant strides in understanding how the protein arginine methyltransferases (PRMTs) “write”, how the methylarginine effectors “read” this PTM, and how these mechanisms work together to regulate multiple facets of gene expression, such as transcription, RNA splicing, and RNA modification. Despite these achievements, significant knowledge gaps still exist. While we have characterized all nine PRMTs (PRMT1-9) and identified numerous arginine-methylated protein substrates, the molecular pathways through which arginine methylation influences gene expression are not yet fully understood. Similarly, although we know reader proteins play a crucial role in transmitting arginine methylation signals to downstream effects, their function and regulation via cell signaling remain somewhat opaque. Moreover, we have yet to fully grasp the role of arginine demethylases in the reversible and dynamic nature of this modification, which can be influenced by various environmental and cellular factors. To fill these gaps in knowledge, our lab intends to address three fundamental questions in arginine methylation and gene regulation through this MIRA award. Specifically, our objectives are to: 1) understand how arginine methylation impacts cellular m6A homeostasis and gene expression, 2) determine how methylarginine readers transmit arginine methylation signals and identify the factors that govern their activity and specificity, and 3) explore to what extent demethylases contribute to the dynamics of arginine methylation. By answering these questions, we anticipate gaining a more comprehensive understanding of arginine methylation and its role in gene regulation. This could lead to potential breakthroughs in translational science, providing valuable insights for treating diseases linked to aberrant arginine methylation.
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