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

doi:10.1016/j.isci.2021.102971

Independent transcriptomic and proteomic regulation by type I and II protein arginine methyltransferases

iScience. 2021 Aug 11;24(9):102971. doi: 10.1016/j.isci.2021.102971. eCollection 2021 Sep 24.

Authors

Maxim I Maron¹, Stephanie M Lehman², Sitaram Gayatri^{3

4

5}, Joseph D DeAngelo¹, Subray Hegde¹, Benjamin M Lorton¹, Yan Sun¹, Dina L Bai², Simone Sidoli¹, Varun Gupta⁶, Matthew R Marunde⁷, James R Bone⁷, Zu-Wen Sun⁷, Mark T Bedford^{3

4

5}, Jeffrey Shabanowitz², Hongshan Chen¹, Donald F Hunt⁸, David Shechter¹

Affiliations

¹ Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
² Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA.
³ Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA.
⁴ Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA.
⁵ Graduate Program in Genetics and Epigenetics, The University of Texas MD Anderson UT Health Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
⁶ Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
⁷ EpiCypher, Inc., Research Triangle Park, NC 27709, USA.
⁸ Departments of Chemistry and Pathology, University of Virginia, Charlottesville, VA 22904, USA.

Abstract

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.

Keywords: cell biology; molecular biology.

Abstract

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