title: ATRX Plays a Key Role in Maintaining Silencing at Interstitial Heterochromatic Loci and Imprinted Genes.
abstract: Histone H3.3 is a replication-independent histone variant, which replaces histones that are turned over throughout the entire cell cycle. H3.3 deposition at euchromatin is dependent on HIRA, whereas ATRX/Daxx deposits H3.3 at pericentric heterochromatin and telomeres. The role of H3.3 at heterochromatic regions is unknown, but mutations in the ATRX/Daxx/H3.3 pathway are linked to aberrant telomere lengthening in certain cancers. In this study, we show that ATRX-dependent deposition of H3.3 is not limited to pericentric heterochromatin and telomeres but also occurs at heterochromatic sites throughout the genome. Notably, ATRX/H3.3 specifically localizes to silenced imprinted alleles in mouse ESCs. ATRX KO cells failed to deposit H3.3 at these sites, leading to loss of the H3K9me3 heterochromatin modification, loss of repression, and aberrant allelic expression. We propose a model whereby ATRX-dependent deposition of H3.3 into heterochromatin is normally required to maintain the memory of silencing at imprinted loci.
authors: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors: Hsiao P J
authors: HP
authors: Voon
authors: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors: Jim R
authors: JR
authors: Hughes
authors: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors: Christina
authors: C
authors: Rode
authors: Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany.
authors: Inti A
authors: IA
authors: De La Rosa-Velázquez
authors: Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany.
authors: Thomas
authors: T
authors: Jenuwein
authors: Institute of Molecular Genetics of Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS), 34293 Montpellier, France.
authors: Robert
authors: R
authors: Feil
authors: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors: Douglas R
authors: DR
authors: Higgs
authors: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK. Electronic address: richard.gibbons@ndcls.ox.ac.uk.
authors: Richard J
authors: RJ
authors: Gibbons
mesh_terms: D000818:Animals; D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D055786:Gene Knockout Techniques; D020868:Gene Silencing / Q000502:physiology*; D056426:Genetic Loci; D006570:Heterochromatin / Q000378:metabolism; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D000075924:X-linked Nuclear Protein
chemical_list: D006570:Heterochromatin; D006657:Histones; D009687:Nuclear Proteins; D004265:DNA Helicases; C490462:Atrx protein, mouse; D000075924:X-linked Nuclear Protein