Joanna Wysocka ¹, C. David Allis ¹, and Scott Coonrod ²

1 Laboratory of Chromatin Biology, Rockefeller University, Box 78, 1230 York Avenue, New York, NY 10021, USA, ² Department of Genetic Medicine, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA

FIGURES

Figure 1. Sites of arginine methylation on histone H3 and H4. CARM1 methylates arginine residues 2, 17, 26, on histone H3 (larger arrowhead indicates H3R17, the major CARM1 target site). PRMT1 methylates arginine 3 on histone H4. PRMT5 methylates arginine 8 on histone H3 and arginine 3 on histone H4. CARM1- and PRMT1-catalyzed asymmetric dimethylarginine modifications activate gene expression (green) while the PRMT5-catalyzed symmetric dimethylarginine modification represses gene activity (red). It remains to be determined whether arginine 17, 19, and 22 on histone H4 and possibly other arginine residues within the histone H3 and H4 core peptide sequence are methylated. The "basic patch" (residues 16 through 20) on the histone H4 tail is involved in regulating higher order chromatin structure.

Figure 2. Role of PRMT1 and CARM1 in nuclear receptor-mediated transcriptional activation. A. Recruitment of the ligand-activated nuclear receptor (NR) to the hormone response element (HRE). B. Association of the primary coactivator p160 with NR leads to the corecruitment of secondary activators like PRMT1 and p300. Methylation of H4R3 by PRMT1 (blue circle = methyl modification) stimulates acetyltransferase activity of p300 (green pentagon = acetyl modification), but acetylation of H4 by p300 inhibits H4 R3 methylation by PRMT1. C. Acetylation of histone H3 by p300 (green pentagon = acetyl modification) enhances CARM1 methylation of H3R17 (red circle = methyl modification). CARM1 associates with Brg1/hBrm remodeling complex and stimulates its ATPase activity. Histone tails methylated on arginines may also serve as a binding platform for the yet unknown downstream effectors (X and Y). D. Assembly of the coactivatory complex on HRE, histone modifications, and chromatin remodeling lead to the activation of transcription of nuclear hormone-dependent genes.

Figure 3. Model of antagonistic regulation of transcription by PRMT1 and PADI4. A. Following recruitment by estrogen receptor to the pS2 gene promoter, PRMT1 methylates histone H4R3 leading to chromatin remodeling and increased template accessibility. Basal transcriptional machinery (RNA polymerase II complex) then associates with chromatin template and activates transcription. B. Subsequently, following recruitment to the promoter, PADI4 then catalyzes the conversion of methylarginine (MeArg) to citrulline (Cit) releasing methylamine (MeNH₃). Citrullination of histone methylarginine residues decreases the ability of transcriptional machinery to bind to chromatin template thereby repressing transcription. PRMT1 - Protein arginine methyltransferase 1. CARM1 - Coactivator-associated arginine methyltransferase 1. pS2 gene - estrogen-responsive.