title: Dynamic recruitment of Ets1 to both nucleosome-occupied and -depleted enhancer regions mediates a transcriptional program switch during early T-cell differentiation.
abstract: Ets1 is a sequence-specific transcription factor that plays an important role during hematopoiesis, and is essential for the transition of CD4(-)/CD8(-) double negative (DN) to CD4(+)/CD8(+) double positive (DP) thymocytes. Using genome-wide and functional approaches, we investigated the binding properties, transcriptional role and chromatin environment of Ets1 during this transition. We found that while Ets1 binding at distal sites was associated with active genes at both DN and DP stages, its enhancer activity was attained at the DP stage, as reflected by levels of the core transcriptional hallmarks H3K4me1/3, RNA Polymerase II and eRNA. This dual, stage-specific ability reflected a switch from non-T hematopoietic toward T-cell specific gene expression programs during the DN-to-DP transition, as indicated by transcriptome analyses of Ets1(-/-) thymic cells. Coincidentally, Ets1 associates more specifically with Runx1 in DN and with TCF1 in DP cells. We also provide evidence that Ets1 predominantly binds distal nucleosome-occupied regions in DN and nucleosome-depleted regions in DP. Finally and importantly, we demonstrate that Ets1 induces chromatin remodeling by displacing H3K4me1-marked nucleosomes. Our results thus provide an original model whereby the ability of a transcription factor to bind nucleosomal DNA changes during differentiation with consequences on its cognate enhancer activity.
authors.affiliation: CIML CNRS UMR7280, Case 906, Campus de Luminy, Marseille F-13009, France CIML INSERM U1104, Case 906, Campus de Luminy, Marseille F-13009, France Aix-Marseille University, 58 Boulevard Charles Livon, Marseille F-13284, France Inserm U1090, Technological Advances for Genomics and Clinics (TAGC), Marseille F-13009, France Aix-Marseille University UMR-S 1090, TAGC, Marseille F-13009, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cauchy
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS UMR5535, 1919 Route de Mende, Montpellier F-34293, France.
authors.forename: Muhammad A
authors.initials: MA
authors.lastname: Maqbool
authors.affiliation: CIML CNRS UMR7280, Case 906, Campus de Luminy, Marseille F-13009, France CIML INSERM U1104, Case 906, Campus de Luminy, Marseille F-13009, France Aix-Marseille University, 58 Boulevard Charles Livon, Marseille F-13284, France.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Zacarias-Cabeza
authors.affiliation: Inserm U1090, Technological Advances for Genomics and Clinics (TAGC), Marseille F-13009, France Aix-Marseille University UMR-S 1090, TAGC, Marseille F-13009, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vanhille
authors.affiliation: CIML CNRS UMR7280, Case 906, Campus de Luminy, Marseille F-13009, France CIML INSERM U1104, Case 906, Campus de Luminy, Marseille F-13009, France Aix-Marseille University, 58 Boulevard Charles Livon, Marseille F-13284, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Koch
authors.affiliation: CIML CNRS UMR7280, Case 906, Campus de Luminy, Marseille F-13009, France CIML INSERM U1104, Case 906, Campus de Luminy, Marseille F-13009, France Aix-Marseille University, 58 Boulevard Charles Livon, Marseille F-13284, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Fenouil
authors.affiliation: Centre Nacional D'Anàlisi Genòmica, Parc Científic de Barcelona, Baldiri i Reixac 4, Barcelona ES-08028, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Gut
authors.affiliation: Centre Nacional D'Anàlisi Genòmica, Parc Científic de Barcelona, Baldiri i Reixac 4, Barcelona ES-08028, Spain.
authors.forename: Ivo
authors.initials: I
authors.lastname: Gut
authors.affiliation: CIML CNRS UMR7280, Case 906, Campus de Luminy, Marseille F-13009, France CIML INSERM U1104, Case 906, Campus de Luminy, Marseille F-13009, France Aix-Marseille University, 58 Boulevard Charles Livon, Marseille F-13284, France.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Santana
authors.affiliation: Inserm U1090, Technological Advances for Genomics and Clinics (TAGC), Marseille F-13009, France Aix-Marseille University UMR-S 1090, TAGC, Marseille F-13009, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Griffon
authors.affiliation: Inserm U1090, Technological Advances for Genomics and Clinics (TAGC), Marseille F-13009, France Aix-Marseille University UMR-S 1090, TAGC, Marseille F-13009, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Imbert
authors.affiliation: INSERM UMR 1126 Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris F-75475, France.
authors.forename: Carolina
authors.initials: C
authors.lastname: Moraes-Cabé
authors.affiliation: INSERM UMR 1126 Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris F-75475, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Bories
authors.affiliation: CIML CNRS UMR7280, Case 906, Campus de Luminy, Marseille F-13009, France CIML INSERM U1104, Case 906, Campus de Luminy, Marseille F-13009, France Aix-Marseille University, 58 Boulevard Charles Livon, Marseille F-13284, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Ferrier
authors.affiliation: Inserm U1090, Technological Advances for Genomics and Clinics (TAGC), Marseille F-13009, France Aix-Marseille University UMR-S 1090, TAGC, Marseille F-13009, France salvatore.spicuglia@inserm.fr.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Spicuglia
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS UMR5535, 1919 Route de Mende, Montpellier F-34293, France jean-christophe.andrau@igmm.cnrs.fr.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Andrau
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009707:Nucleosomes / Q000235:genetics* / Q000378:metabolism; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism*; D012319:RNA Polymerase II / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013601:T-Lymphocytes / Q000166:cytology*
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; C494042:Ets1 protein, mouse; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D009707:Nucleosomes; D050784:Proto-Oncogene Protein c-ets-1; C493726:Runx1 protein, mouse; D012319:RNA Polymerase II