20210906 Ho MC Epub

The Macromolecular Complexes of Histones Affect Protein Arginine Methyltransferase Activities

The Macromolecular Complexes of Histones Affect Protein Arginine Methyltransferase Activities

J Biol Chem. 2021 Oct 20; 297(4), 101123.
doi: 10.1016/j.jbc.2021.101123


Fulton MD, Cao M, Ho MC, Zhao X, Zheng YG


Histone arginine methylation is a key post-translational modification that mediates epigenetic events that activate or repress gene transcription. Protein arginine methyltransferases (PRMTs) are the driving force for the process of arginine methylation, and the core histone proteins have been shown to be substrates for most PRMT family members. However, previous reports of the enzymatic activities of PRMTs on histones in the context of nucleosomes seem contradictory. Moreover, what governs nucleosomal substrate recognition of different PRMT members is not understood. We sought to address this key biological question by examining how different macromolecular contexts where the core histones reside may regulate arginine methylation catalyzed by individual PRMT members (i.e., PRMT1, -3, -4, -5, -6, -7, and -8). Our results demonstrated the substrate context exhibits a huge impact on the histone arginine methylation activity of PRMTs. Although all the tested PRMTs methylate multiple free histones individually, they show a preference for one particular histone substrate in the context of the histone octamer. We found that PRMT1, -3, -5, -6, -7, and -8 preferentially methylate histone H4, while PRMT4/CARM1 prefers histone H3. Importantly, neither reconstituted nor cell-extracted mononucleosomes could be methylated by any PRMTs tested. Structural analysis suggested that the electrostatic interaction may play a mechanistic role in priming the substrates for methylation by PRMT enzymes. Taken together, this work expands our knowledge on the molecular mechanisms of PRMT substrate recognition and has important implications for understanding cellular dynamics and kinetics of histone arginine methylation in regulating gene transcription and other chromatin-templated processes.