title: CARM1 automethylation is controlled at the level of alternative splicing.
abstract: Co-activator-associated arginine methyltransferase 1 (CARM1) is subjected to multiple post-translational modifications. Our previous finding that automethylation of CARM1 is essential for regulation of transcription and pre-mRNA splicing prompted us to investigate how automethylation is regulated. Here, we report that automethylation is regulated by alternative splicing of CARM1 mRNA to remove exon 15, containing the automethylation site. Specifically, we find that two major alternative transcripts encoding full-length CARM1 (CARM1FL) and CARM1 with exon 15 deleted (CARM1ΔE15) exist in cells, and each transcript produces the expected protein. Further biochemical characterizations of the automethylation-defective mutant and CARM1ΔE15 reveal overlapping yet different properties. Interestingly, other arginine methylation substrates also have missing exons encompassing the site(s) of methylation, suggesting that protein arginine methylation level may, in general, be controlled by the alternative splicing mechanism. Finally, we observed differential distribution of CARM1FL and CARM1ΔE15 in epithelial and stromal cells in normal mouse mammary gland. Thus, alternative splicing not only serves as the determinant for CARM1 automethylation but also generates cell type-specific isoforms that might regulate normal ERα biology in the mammary gland.
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, 1400 University Avenue, Madison, WI 53706, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Purin
authors.initials: P
authors.lastname: Charoensuksai
authors.forename: Nikole J
authors.initials: NJ
authors.lastname: Watson
authors.forename: Xing
authors.initials: X
authors.lastname: Wang
authors.forename: Zibo
authors.initials: Z
authors.lastname: Zhao
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Coriano
authors.forename: Leslie R
authors.initials: LR
authors.lastname: Kerr
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D000906:Antibodies; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000201:enzymology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000201:enzymology; D008745:Methylation; D051379:Mice; D008807:Mice, Inbred BALB C; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017154:Stromal Cells / Q000201:enzymology; D014158:Transcription, Genetic
chemical_list: D000906:Antibodies; D047628:Estrogen Receptor alpha; D007527:Isoenzymes; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1