An H3K9/S10 methyl-phospho switch modulates Polycomb and Pol II binding at repressed genes during differentiation

• Published in: Molecular biology of the cell 2014-03, Vol.25 (6), p.904-915
• Main Authors: Sabbattini, Pierangela, Sjoberg, Marcela, Nikic, Svetlana, Frangini, Alberto, Holmqvist, Per-Henrik, Kunowska, Natalia, Carroll, Tom, Brookes, Emily, Arthur, Simon J, Pombo, Ana, Dillon, Niall
• Format: Article
• Language: English
• Subjects: Animals; Aurora Kinase B - antagonists & inhibitors; Aurora Kinase B - genetics; Aurora Kinase B - metabolism; B-Lymphocytes - cytology; B-Lymphocytes - metabolism; Binding Sites; Cell Differentiation - genetics; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Epigenesis, Genetic; Histones - genetics; Histones - metabolism; Lymphocyte Activation; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; Methylation; Mice; Osteoblasts - cytology; Osteoblasts - metabolism; Phosphorylation; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - metabolism; Polycomb-Group Proteins - genetics; Polycomb-Group Proteins - metabolism; Promoter Regions, Genetic; Protein Binding; Protein Kinase Inhibitors - pharmacology; Ribosomal Protein S6 Kinases, 90-kDa - antagonists & inhibitors; Ribosomal Protein S6 Kinases, 90-kDa - genetics; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; RNA Polymerase II - genetics; RNA Polymerase II - metabolism; Signal Transduction; Spleen - cytology; Spleen - metabolism
• ISSN: 1059-1524; 1939-4586
• DOI: 10.1091/mbc.e13-10-0628

Methylated histones H3K9 and H3K27 are canonical epigenetic silencing modifications in metazoan organisms, but the relationship between the two modifications has not been well characterized. H3K9me3 coexists with H3K27me3 in pluripotent and differentiated cells. However, we find that the functioning of H3K9me3 is altered by H3S10 phosphorylation in differentiated postmitotic osteoblasts and cycling B cells. Deposition of H3K9me3/S10ph at silent genes is partially mediated by the mitogen- and stress-activated kinases (MSK1/2) and the Aurora B kinase. Acquisition of H3K9me3/S10ph during differentiation correlates with loss of paused S5 phosphorylated RNA polymerase II, which is present on Polycomb-regulated genes in embryonic stem cells. Reduction of the levels of H3K9me3/S10ph by kinase inhibition results in increased binding of RNAPIIS5ph and the H3K27 methyltransferase Ezh1 at silent promoters. Our results provide evidence of a novel developmentally regulated methyl-phospho switch that modulates Polycomb regulation in differentiated cells and stabilizes repressed states.