Independent transcriptomic and proteomic regulation by type I and II protein arginine methyltransferases
Maxim I. Maron,
Stephanie M. Lehman,
Sitaram Gayatri,
Joseph D. DeAngelo,
Subray Hegde,
Benjamin M. Lorton,
Yan Sun,
Dina L. Bai,
Simone Sidoli,
Varun Gupta,
Matthew R. Marunde,
James R. Bone,
Zu-Wen Sun,
Mark T. Bedford,
Jeffrey Shabanowitz,
Hongshan Chen,
Donald F. Hunt,
David Shechter
Affiliations
Maxim I. Maron
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Stephanie M. Lehman
Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA
Sitaram Gayatri
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA; Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA; Graduate Program in Genetics and Epigenetics, The University of Texas MD Anderson UT Health Graduate School of Biomedical Sciences, Houston, TX 77030, USA
Joseph D. DeAngelo
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Subray Hegde
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Benjamin M. Lorton
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Yan Sun
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Dina L. Bai
Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA
Simone Sidoli
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Varun Gupta
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Matthew R. Marunde
EpiCypher, Inc., Research Triangle Park, NC 27709, USA
James R. Bone
EpiCypher, Inc., Research Triangle Park, NC 27709, USA
Zu-Wen Sun
EpiCypher, Inc., Research Triangle Park, NC 27709, USA
Mark T. Bedford
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA; Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA; Graduate Program in Genetics and Epigenetics, The University of Texas MD Anderson UT Health Graduate School of Biomedical Sciences, Houston, TX 77030, USA
Jeffrey Shabanowitz
Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA
Hongshan Chen
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Corresponding author
Donald F. Hunt
Departments of Chemistry and Pathology, University of Virginia, Charlottesville, VA 22904, USA; Corresponding author
David Shechter
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Corresponding author
Summary: Protein arginine methyltransferases (PRMTs) catalyze the post-translational monomethylation (Rme1), asymmetric (Rme2a), or symmetric (Rme2s) dimethylation of arginine. To determine the cellular consequences of type I (Rme2a) and II (Rme2s) PRMTs, we developed and integrated multiple approaches. First, we determined total cellular dimethylarginine levels, revealing that Rme2s was ∼3% of total Rme2 and that this percentage was dependent upon cell type and PRMT inhibition status. Second, we quantitatively characterized in vitro substrates of the major enzymes and expanded upon PRMT substrate recognition motifs. We also compiled our data with publicly available methylarginine-modified residues into a comprehensive database. Third, we inhibited type I and II PRMTs and performed proteomic and transcriptomic analyses to reveal their phenotypic consequences. These experiments revealed both overlapping and independent PRMT substrates and cellular functions. Overall, this study expands upon PRMT substrate diversity, the arginine methylome, and the complex interplay of type I and II PRMTs.