title: Polycomb group protein displacement and gene activation through MSK-dependent H3K27me3S28 phosphorylation.
abstract: Epigenetic regulation of chromatin structure is essential for the expression of genes determining cellular specification and function. The Polycomb repressive complex 2 (PRC2) di- and trimethylates histone H3 on lysine 27 (H3K27me2/me3) to establish repression of specific genes in embryonic stem cells and during differentiation. How the Polycomb group (PcG) target genes are regulated by environmental cues and signaling pathways is quite unexplored. Here, we show that the mitogen- and stress-activated kinases (MSK), through a mechanism that involves promoter recruitment, histone H3K27me3S28 phosphorylation, and displacement of PcG proteins, lead to gene activation. We present evidence that the H3K27me3S28 phosphorylation is functioning in response to stress signaling, mitogenic signaling, and retinoic acid (RA)-induced neuronal differentiation. We propose that MSK-mediated H3K27me3S28 phosphorylation serves as a mechanism to activate a subset of PcG target genes determined by the biological stimuli and thereby modulate the gene expression program determining cell fate.
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N, Denmark.
authors.forename: Simmi Suman
authors.initials: SS
authors.lastname: Gehani
authors.forename: Shuchi
authors.initials: S
authors.lastname: Agrawal-Singh
authors.forename: Nikolaj
authors.initials: N
authors.lastname: Dietrich
authors.forename: Nicolaj Strøyer
authors.initials: NS
authors.lastname: Christophersen
authors.forename: Kristian
authors.initials: K
authors.lastname: Helin
authors.forename: Klaus
authors.initials: K
authors.lastname: Hansen
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics; D000841:Anisomycin / Q000494:pharmacology; D000906:Antibodies / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D053595:Embryonic Stem Cells / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D006367:HeLa Cells; D006657:Histones / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D008938:Mitosis / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D063146:Polycomb-Group Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000502:physiology; D021381:Protein Transport / Q000502:physiology*; D012097:Repressor Proteins / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D000906:Antibodies; D002843:Chromatin; D006657:Histones; D010455:Peptides; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D012694:Serine; D000841:Anisomycin; C115634:RPS6KA4 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D008239:Lysine