title: MicroRNAs of the miR-290-295 Family Maintain Bivalency in Mouse Embryonic Stem Cells.
abstract: Numerous developmentally regulated genes in mouse embryonic stem cells (ESCs) are marked by both active (H3K4me3)- and polycomb group (PcG)-mediated repressive (H3K27me3) histone modifications. This bivalent state is thought to be important for transcriptional poising, but the mechanisms that regulate bivalent genes and the bivalent state remain incompletely understood. Examining the contribution of microRNAs (miRNAs) to the regulation of bivalent genes, we found that the miRNA biogenesis enzyme DICER was required for the binding of the PRC2 core components EZH2 and SUZ12, and for the presence of the PRC2-mediated histone modification H3K27me3 at many bivalent genes. Genes that lost bivalency were preferentially upregulated at the mRNA and protein levels. Finally, reconstituting Dicer-deficient ESCs with ESC miRNAs restored bivalent gene repression and PRC2 binding at formerly bivalent genes. Therefore, miRNAs regulate bivalent genes and the bivalent state itself.
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK; Epigenetics Section, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Bryony
authors.initials: B
authors.lastname: Graham
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK; Epigenetics Section, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK.
authors.forename: Antoine
authors.initials: A
authors.lastname: Marcais
authors.affiliation: Epigenetics Section, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK.
authors.forename: Gopuraja
authors.initials: G
authors.lastname: Dharmalingam
authors.affiliation: Epigenetics Section, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Carroll
authors.affiliation: Laboratory of Immunology, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Chryssa
authors.initials: C
authors.lastname: Kanellopoulou
authors.affiliation: Department of Proteomics and Signal Transduction, Max-Planck Institute for Biochemistry, 82152 Martinsried, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Graumann
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
authors.forename: Tatyana B
authors.initials: TB
authors.lastname: Nesterova
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK; Epigenetics Section, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Bermange
authors.affiliation: Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Oxford OX3 7DQ, UK.
authors.forename: Pijus
authors.initials: P
authors.lastname: Brazauskas
authors.affiliation: MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Barbara
authors.initials: B
authors.lastname: Xella
authors.affiliation: Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Oxford OX3 7DQ, UK.
authors.forename: Skirmantas
authors.initials: S
authors.lastname: Kriaucionis
authors.affiliation: MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Higgs
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Brockdorff
authors.affiliation: Department of Proteomics and Signal Transduction, Max-Planck Institute for Biochemistry, 82152 Martinsried, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mann
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK; Epigenetics Section, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK.
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Fisher
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK; Epigenetics Section, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK. Electronic address: matthias.merkenschlager@csc.mrc.ac.uk.
authors.forename: Matthias
authors.initials: M
authors.lastname: Merkenschlager
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D042421:Histone Code / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D000066450:Mouse Embryonic Stem Cells / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics*; D011401:Promoter Regions, Genetic; D043244:Ribonuclease III / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: C547384:MIRN290 microRNA, mouse; C561933:MIRN295 microRNA, mouse; D035683:MicroRNAs; C494163:Suz12 protein, mouse; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases