title: C/EBPα Activates Pre-existing and De Novo Macrophage Enhancers during Induced Pre-B Cell Transdifferentiation and Myelopoiesis.
abstract: Transcription-factor-induced somatic cell conversions are highly relevant for both basic and clinical research yet their mechanism is not fully understood and it is unclear whether they reflect normal differentiation processes. Here we show that during pre-B-cell-to-macrophage transdifferentiation, C/EBPα binds to two types of myeloid enhancers in B cells: pre-existing enhancers that are bound by PU.1, providing a platform for incoming C/EBPα; and de novo enhancers that are targeted by C/EBPα, acting as a pioneer factor for subsequent binding by PU.1. The order of factor binding dictates the upregulation kinetics of nearby genes. Pre-existing enhancers are broadly active throughout the hematopoietic lineage tree, including B cells. In contrast, de novo enhancers are silent in most cell types except in myeloid cells where they become activated by C/EBP factors. Our data suggest that C/EBPα recapitulates physiological developmental processes by short-circuiting two macrophage enhancer pathways in pre-B cells.
authors.affiliation: Center for Genomic Regulation and Pompeu Fabra University, 08003 Barcelona, Spain. Electronic address: chris.vanoevelen@crg.eu.
authors.forename: Chris
authors.initials: C
authors.lastname: van Oevelen
authors.affiliation: Ecole Normale Supérieure, Institut de Biologie de l'ENS, INSERM, U1024, Centre National de la Recherche Scientifique (CNRS) 8197, 75005 Paris, France.
authors.forename: Samuel
authors.initials: S
authors.lastname: Collombet
authors.affiliation: Center for Genomic Regulation and Pompeu Fabra University, 08003 Barcelona, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Vicent
authors.affiliation: School of Cancer Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Maarten
authors.initials: M
authors.lastname: Hoogenkamp
authors.affiliation: CNRS, Aix-Marseille Université, IGS UMR7256, 13288 Marseille, France.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Lepoivre
authors.affiliation: Harvard Medical School, Children's Hospital, Boston, MA 02115, USA.
authors.forename: Aimee
authors.initials: A
authors.lastname: Badeaux
authors.affiliation: Center for Genomic Regulation and Pompeu Fabra University, 08003 Barcelona, Spain.
authors.forename: Lars
authors.initials: L
authors.lastname: Bussmann
authors.affiliation: Center for Genomic Regulation and Pompeu Fabra University, 08003 Barcelona, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Sardina
authors.affiliation: Ecole Normale Supérieure, Institut de Biologie de l'ENS, INSERM, U1024, Centre National de la Recherche Scientifique (CNRS) 8197, 75005 Paris, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Thieffry
authors.affiliation: Center for Genomic Regulation and Pompeu Fabra University, 08003 Barcelona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Beato
authors.affiliation: Harvard Medical School, Children's Hospital, Boston, MA 02115, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
authors.affiliation: School of Cancer Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Constanze
authors.initials: C
authors.lastname: Bonifer
authors.affiliation: Center for Genomic Regulation and Pompeu Fabra University, 08003 Barcelona, Spain. Electronic address: thomas.graf@crg.eu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Graf
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D054338:Cell Transdifferentiation; D006801:Humans; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism*; D038042:Myelopoiesis; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism*
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D050783:Proto-Oncogene Proteins c-ets