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Abstract
Histone methylation plays an important regulatory role in chromatin restructuring and RNA transcription. Arginine methylation that is enzymatically catalyzed by the family of protein arginine methyltransferases (PRMTs) can either activate or repress gene expression depending on cellular contexts. Given the strong correlation of PRMTs with pathophysiology, great interest is seen in understanding the molecular mechanisms of PRMTs in diseases and in developing potent PRMT inhibitors. We hypothesized that local chemical modifications to the substrate as well as the macromolecular context of the substrate are mechanisms that can regulated arginine methylation. Specifically, we determined how post-translational modifications on the histone H4 N-terminal tail regulates type I and type II PRMT catalysis. We observed that local chemical modifications such as phosphorylation, acetylation, and methylation can inhibit, stimulate, or have no effect on PRMT catalysis. Moreover, the -amine of Lys-5 in the histone H4 sequence is important for asymmetric and symmetric dimethylation. Since histones can form an octamer and wrap with DNA to form the basic unit of chromatin, the nucleosome, we sought to answer how these different macromolecular contexts may regulate arginine methylation by PRMT1, -3, -4, -5, -6, -7, and -8. We observed that all the PRMTs will methylate at least two types of histones individually, yet most of the PRMTs demonstrate a preference for one histone in the context of the histone octamer. This body of work highlights the underlying mechanistic differences in substrate recognition among different PRMTs and offers new directions for future research.