title: C/EBPα creates elite cells for iPSC reprogramming by upregulating Klf4 and increasing the levels of Lsd1 and Brd4.
abstract: Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) is typically inefficient and has been explained by elite-cell and stochastic models. We recently reported that B cells exposed to a pulse of C/EBPα (Bα' cells) behave as elite cells, in that they can be rapidly and efficiently reprogrammed into iPSCs by the Yamanaka factors OSKM. Here we show that C/EBPα post-transcriptionally increases the abundance of several hundred proteins, including Lsd1, Hdac1, Brd4, Med1 and Cdk9, components of chromatin-modifying complexes present at super-enhancers. Lsd1 was found to be required for B cell gene silencing and Brd4 for the activation of the pluripotency program. C/EBPα also promotes chromatin accessibility in pluripotent cells and upregulates Klf4 by binding to two haematopoietic enhancers. Bα' cells share many properties with granulocyte/macrophage progenitors, naturally occurring elite cells that are obligate targets for leukaemic transformation, whose formation strictly requires C/EBPα.
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.|Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain.
authors.forename: Bruno
authors.initials: B
authors.lastname: Di Stefano
authors.affiliation: Institut de Biologie de l'Ecole Normale Supérieure (IBENS), CNRS UMR8197, INSERM U1024, Ecole Normale Supérieure, PSL Research University, F-75005 Paris, France.
authors.forename: Samuel
authors.identifier: http://orcid.org/0000-0002-0111-7177
authors.initials: S
authors.lastname: Collombet
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Ole Maaløes Vej 5, Copenhagen 2200, Denmark.|Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen 2200, Denmark.|Danish Stem Cell Center (DanStem), Faculty of Health Sciences, University of Copenhagen, 3B Blegdamsvej, Copenhagen 2200, Denmark.
authors.forename: Janus Schou
authors.identifier: http://orcid.org/0000-0001-6135-5815
authors.initials: JS
authors.lastname: Jakobsen
authors.affiliation: Max Planck Institute of Biochemistry, 82152 Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wierer
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.|Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Sardina
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.|Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lackner
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.|Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain.
authors.forename: Ralph
authors.initials: R
authors.lastname: Stadhouders
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.|Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Segura-Morales
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.|Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain.
authors.forename: Mirko
authors.initials: M
authors.lastname: Francesconi
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.|Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain.
authors.forename: Francesco
authors.initials: F
authors.lastname: Limone
authors.affiliation: Max Planck Institute of Biochemistry, 82152 Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mann
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Ole Maaløes Vej 5, Copenhagen 2200, Denmark.|Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen 2200, Denmark.|Danish Stem Cell Center (DanStem), Faculty of Health Sciences, University of Copenhagen, 3B Blegdamsvej, Copenhagen 2200, Denmark.
authors.forename: Bo
authors.identifier: http://orcid.org/0000-0001-6043-0844
authors.initials: B
authors.lastname: Porse
authors.affiliation: Institut de Biologie de l'Ecole Normale Supérieure (IBENS), CNRS UMR8197, INSERM U1024, Ecole Normale Supérieure, PSL Research University, F-75005 Paris, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Thieffry
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.|Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain.
authors.forename: Thomas
authors.initials: T
authors.lastname: Graf
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D015153:Blotting, Western; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D063990:Gene Ontology; D057809:HEK293 Cells; D056466:Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000066450:Mouse Embryonic Stem Cells / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D000092468:Bromodomain Containing Proteins
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D056466:Histone Demethylases; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; C504076:KDM1a protein, mouse