title: An H3K9/S10 methyl-phospho switch modulates Polycomb and Pol II binding at repressed genes during differentiation.
abstract: 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.
authors.affiliation: Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom Genome Function Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom MRC Protein Phosphorylation Unit, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, United Kingdom.
authors.forename: Pierangela
authors.initials: P
authors.lastname: Sabbattini
authors.forename: Marcela
authors.initials: M
authors.lastname: Sjoberg
authors.forename: Svetlana
authors.initials: S
authors.lastname: Nikic
authors.forename: Alberto
authors.initials: A
authors.lastname: Frangini
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Holmqvist
authors.forename: Natalia
authors.initials: N
authors.lastname: Kunowska
authors.forename: Tom
authors.initials: T
authors.lastname: Carroll
authors.forename: Emily
authors.initials: E
authors.lastname: Brookes
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Arthur
authors.forename: Ana
authors.initials: A
authors.lastname: Pombo
authors.forename: Niall
authors.initials: N
authors.lastname: Dillon
mesh_terms: D000818:Animals; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D001665:Binding Sites; D002454:Cell Differentiation / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D044127:Epigenesis, Genetic; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D008213:Lymphocyte Activation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D008745:Methylation; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012319:RNA Polymerase II / Q000235:genetics* / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000378:metabolism
chemical_list: D006657:Histones; D063146:Polycomb-Group Proteins; D047428:Protein Kinase Inhibitors; C498408:Ezh1 protein, mouse; D063151:Polycomb Repressive Complex 2; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C485459:Rps6ka4 protein, mouse; C116919:mitogen and stress-activated protein kinase 1; D012319:RNA Polymerase II