title: Atad2 is a generalist facilitator of chromatin dynamics in embryonic stem cells.
abstract: Although the conserved AAA ATPase and bromodomain factor, ATAD2, has been described as a transcriptional co-activator upregulated in many cancers, its function remains poorly understood. Here, using a combination of ChIP-seq, ChIP-proteomics, and RNA-seq experiments in embryonic stem cells where Atad2 is normally highly expressed, we found that Atad2 is an abundant nucleosome-bound protein present on active genes, associated with chromatin remodelling, DNA replication, and DNA repair factors. A structural analysis of its bromodomain and subsequent investigations demonstrate that histone acetylation guides ATAD2 to chromatin, resulting in an overall increase of chromatin accessibility and histone dynamics, which is required for the proper activity of the highly expressed gene fraction of the genome. While in exponentially growing cells Atad2 appears dispensable for cell growth, in differentiating ES cells Atad2 becomes critical in sustaining specific gene expression programmes, controlling proliferation and differentiation. Altogether, this work defines Atad2 as a facilitator of general chromatin-templated activities such as transcription.
authors.affiliation: INSERM, U823; Université Grenoble Alpes; Institut Albert Bonniot Grenoble, F-38700 Grenoble, France.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Morozumi
authors.affiliation: INSERM, U823; Université Grenoble Alpes; Institut Albert Bonniot Grenoble, F-38700 Grenoble, France.
authors.forename: Fayçal
authors.initials: F
authors.lastname: Boussouar
authors.affiliation: The Chemical Proteomics Center and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Minjia
authors.initials: M
authors.lastname: Tan
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), NDM Research Building, Roosevelt Drive, Oxford OX3 7FZ, UK.
authors.forename: Apirat
authors.initials: A
authors.lastname: Chaikuad
authors.affiliation: INSERM, U823; Université Grenoble Alpes; Institut Albert Bonniot Grenoble, F-38700 Grenoble, France.
authors.forename: Mahya
authors.initials: M
authors.lastname: Jamshidikia
authors.affiliation: Ben May Department of Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Gozde
authors.initials: G
authors.lastname: Colak
authors.affiliation: Ben May Department of Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Huang
authors.initials: H
authors.lastname: He
authors.affiliation: The Chemical Proteomics Center and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Litong
authors.initials: L
authors.lastname: Nie
authors.affiliation: Université Grenoble Alpes/CNRS/CEA, Institut de Biologie Structurale, 38027 Grenoble, France.
authors.forename: Carlo
authors.initials: C
authors.lastname: Petosa
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay, CEN Saclay, 91191 Gif-sur-Yvette, France.
authors.forename: Maud
authors.initials: M
authors.lastname: de Dieuleveult
authors.affiliation: INSERM, U823; Université Grenoble Alpes; Institut Albert Bonniot Grenoble, F-38700 Grenoble, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Curtet
authors.affiliation: INSERM, U823; Université Grenoble Alpes; Institut Albert Bonniot Grenoble, F-38700 Grenoble, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Vitte
authors.affiliation: INSERM, U823; Université Grenoble Alpes; Institut Albert Bonniot Grenoble, F-38700 Grenoble, France.
authors.forename: Clothilde
authors.initials: C
authors.lastname: Rabatel
authors.affiliation: INSERM, U823; Université Grenoble Alpes; Institut Albert Bonniot Grenoble, F-38700 Grenoble, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Debernardi
authors.affiliation: CIRI, International Center for Infectiology Research, EVIR team, INSERM U1111, CNRS, UMR5308, Université de Lyon-1, ENS de Lyon, Lyon, France.
authors.forename: François-Loïc
authors.initials: FL
authors.lastname: Cosset
authors.affiliation: CIRI, International Center for Infectiology Research, EVIR team, INSERM U1111, CNRS, UMR5308, Université de Lyon-1, ENS de Lyon, Lyon, France INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe 'contrôle métabolique des morts cellulaires', Nice 06204, France.
authors.forename: Els
authors.initials: E
authors.lastname: Verhoeyen
authors.affiliation: INSERM, U823; Université Grenoble Alpes; Institut Albert Bonniot Grenoble, F-38700 Grenoble, France.
authors.forename: Anouk
authors.initials: A
authors.lastname: Emadali
authors.affiliation: Boehringer-Ingelheim RCV GmbH & Co KG, Dr. Boehringer Gasse 5-11, A-1121 Vienna, Austria.
authors.forename: Norbert
authors.initials: N
authors.lastname: Schweifer
authors.affiliation: Boehringer-Ingelheim RCV GmbH & Co KG, Dr. Boehringer Gasse 5-11, A-1121 Vienna, Austria.
authors.forename: Davide
authors.initials: D
authors.lastname: Gianni
authors.affiliation: CNAG-Centre for Genomic Regulation (CRG), Baldiri Reixac 4, 08028 Barcelona; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Gut
authors.affiliation: INSERM, U892; Centre de Recherche sur le Cancer Nantes Angers and UMR_S 892; Université d'Angers; Plateforme SNP, Transcriptome & Epigénomique; Centre Hospitalier Universitaire d'Angers, Angers 49000, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Guardiola
authors.affiliation: INSERM, U823; Université Grenoble Alpes; Institut Albert Bonniot Grenoble, F-38700 Grenoble, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Rousseaux
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay, CEN Saclay, 91191 Gif-sur-Yvette, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Gérard
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), NDM Research Building, Roosevelt Drive, Oxford OX3 7FZ, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: The Chemical Proteomics Center and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China Ben May Department of Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Yingming
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: INSERM, U823; Université Grenoble Alpes; Institut Albert Bonniot Grenoble, F-38700 Grenoble, France khochbin@ujf-grenoble.fr.
authors.forename: Saadi
authors.initials: S
authors.lastname: Khochbin
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000107:Acetylation; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D016678:Genome; D005854:Germ Cells / Q000378:metabolism; D006801:Humans; D008297:Male; D009707:Nucleosomes / Q000378:metabolism; D011485:Protein Binding; D040901:Proteomics
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D009707:Nucleosomes; D000251:Adenosine Triphosphatases; C544857:ATAD2 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities
keywords: FACT; Pax3; cancer drug target; epidrug; germ cells; histone chaperone; histone turnover