Genomic Location of PRMT6-Dependent H3R2 Methylation Is Linked to the Transcriptional Outcome of Associated Genes

• Published in: Cell reports (Cambridge) 2018-09, Vol.24 (12), p.3339-3352
• Main Authors: Bouchard, Caroline, Sahu, Peeyush, Meixner, Marion, Nötzold, René Reiner, Rust, Marco B., Kremmer, Elisabeth, Feederle, Regina, Hart-Smith, Gene, Finkernagel, Florian, Bartkuhn, Marek, Savai Pullamsetti, Soni, Nist, Andrea, Stiewe, Thorsten, Philipsen, Sjaak, Bauer, Uta-Maria
• Format: Article
• Language: English
• Subjects: Animals; chromatin; Enhancer Elements, Genetic; gene expression; HEK293 Cells; HeLa Cells; histone arginine methylation; Histone Code; histone modifications; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Histones - chemistry; Histones - metabolism; Humans; Methylation; Mice; Myeloid-Lymphoid Leukemia Protein - genetics; Myeloid-Lymphoid Leukemia Protein - metabolism; neural differentiation; Neurogenesis - genetics; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; pluripotency; posttranslational modifications; protein arginine methyltransferases; Protein Binding; Protein Processing, Post-Translational; Protein-Arginine N-Methyltransferases - genetics; Protein-Arginine N-Methyltransferases - metabolism; Transcriptional Activation; transcriptional regulation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.08.052

Protein arginine methyltransferase 6 (PRMT6) catalyzes asymmetric dimethylation of histone H3 at arginine 2 (H3R2me2a). This mark has been reported to associate with silent genes. Here, we use a cell model of neural differentiation, which upon PRMT6 knockout exhibits proliferation and differentiation defects. Strikingly, we detect PRMT6-dependent H3R2me2a at active genes, both at promoter and enhancer sites. Loss of H3R2me2a from promoter sites leads to enhanced KMT2A binding and H3K4me3 deposition together with increased target gene transcription, supporting a repressive nature of H3R2me2a. At enhancers, H3R2me2a peaks co-localize with the active enhancer marks H3K4me1 and H3K27ac. Here, loss of H3R2me2a results in reduced KMT2D binding and H3K4me1/H3K27ac deposition together with decreased transcription of associated genes, indicating that H3R2me2a also exerts activation functions. Our work suggests that PRMT6 via H3R2me2a interferes with the deposition of adjacent histone marks and modulates the activity of important differentiation-associated genes by opposing transcriptional effects. [Display omitted] •PRMT6 deposits H3R2me2a at promoters as well as enhancers of active genes•H3R2me2a influences the occurrence of adjacent histone marks (H3K4me3, H3K4me1, H3K27ac)•H3R2me2a contributes to gene repression at promoters and gene activation at enhancers•PRMT6/H3R2me2a modulate the transcription of important neural differentiation genes Bouchard et al. identify the genome-wide, PRMT6-dependent occurrence of H3R2me2a in a cell model of neural differentiation. H3R2me2a is localized at promoters and enhancers of active genes and influences the chromatin recruitment of histone lysine methyltransferases. Thereby, H3R2me2a modulates the deposition of adjacent histone H3 marks and regulates the transcriptional output of genes relevant for pluripotency and differentiation.