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Cell Rep. 2018 Sep 18;24(12):3339-3352. doi: 10.1016/j.celrep.2018.08.052.

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

Author information

1
Institute for Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Hans-Meerwein-Strasse 2, BMFZ, 35043 Marburg, Germany.
2
Molecular Neurobiology Group, Institute of Physiological Chemistry, Philipps-University Marburg, Karl-von-Frisch-Strasse 1, 35043 Marburg, Germany.
3
Institute of Molecular Immunology, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 81377 Munich, Germany.
4
Monoclonal Antibody Core Facility, Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
5
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
6
Center for Tumor Biology and Immunology (ZTI), Philipps-University Marburg, Hans-Meerwein-Strasse 3, 35043 Marburg, Germany.
7
Institute for Genetics, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 58-62, 35392 Giessen, Germany.
8
Department of Lung Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Bad Nauheim, Germany.
9
Genomics Core Facility, Philipps-University Marburg, Hans-Meerwein-Strasse 3, 35043 Marburg, Germany.
10
Genomics Core Facility, Philipps-University Marburg, Hans-Meerwein-Strasse 3, 35043 Marburg, Germany; Institute of Molecular Oncology, Philipps-University Marburg, Hans-Meerwein-Strasse 3, 35043 Marburg, Germany.
11
Department of Cell Biology, Erasmus MC, Rotterdam, the Netherlands.
12
Institute for Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Hans-Meerwein-Strasse 2, BMFZ, 35043 Marburg, Germany. Electronic address: bauer@imt.uni-marburg.de.

Abstract

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.

KEYWORDS:

chromatin; gene expression; histone arginine methylation; histone code; histone modifications; neural differentiation; pluripotency; posttranslational modifications; protein arginine methyltransferases; transcriptional regulation

PMID:
30232013
DOI:
10.1016/j.celrep.2018.08.052
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