title: RAR/RXR binding dynamics distinguish pluripotency from differentiation associated cis-regulatory elements.
abstract: In mouse embryonic cells, ligand-activated retinoic acid receptors (RARs) play a key role in inhibiting pluripotency-maintaining genes and activating some major actors of cell differentiation. To investigate the mechanism underlying this dual regulation, we performed joint RAR/RXR ChIP-seq and mRNA-seq time series during the first 48 h of the RA-induced Primitive Endoderm (PrE) differentiation process in F9 embryonal carcinoma (EC) cells. We show here that this dual regulation is associated with RAR/RXR genomic redistribution during the differentiation process. In-depth analysis of RAR/RXR binding sites occupancy dynamics and composition show that in undifferentiated cells, RAR/RXR interact with genomic regions characterized by binding of pluripotency-associated factors and high prevalence of the non-canonical DR0-containing RA response element. By contrast, in differentiated cells, RAR/RXR bound regions are enriched in functional Sox17 binding sites and are characterized with a higher frequency of the canonical DR5 motif. Our data offer an unprecedentedly detailed view on the action of RA in triggering pluripotent cell differentiation and demonstrate that RAR/RXR action is mediated via two different sets of regulatory regions tightly associated with cell differentiation status.
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon1, CGphiMC UMR CNRS 5534, 69622 Villeurbanne, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Chatagnon
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon1, LBBE UMR CNRS 5558, 69622 Villeurbanne, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Veber
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon1, CGphiMC UMR CNRS 5534, 69622 Villeurbanne, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Morin
authors.affiliation: Université d'Evry-Val d'Essonne, IBISC EA 4526, 91037 Evry, France.
authors.forename: Justin
authors.initials: J
authors.lastname: Bedo
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon1, CGphiMC UMR CNRS 5534, 69622 Villeurbanne, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Triqueneaux
authors.affiliation: IGFL, Université de Lyon, Université Lyon 1, CNRS, INRA; Ecole Normale Supérieure de Lyon, 69007 Lyon, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Sémon
authors.affiliation: IGFL, Université de Lyon, Université Lyon 1, CNRS, INRA; Ecole Normale Supérieure de Lyon, 69007 Lyon, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Laudet
authors.affiliation: Université d'Evry-Val d'Essonne, IBISC EA 4526, 91037 Evry, France.
authors.forename: Florence
authors.initials: F
authors.lastname: d'Alché-Buc
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon1, CGphiMC UMR CNRS 5534, 69622 Villeurbanne, France gerard.benoit@univ-lyon1.fr.
authors.forename: Gérard
authors.initials: G
authors.lastname: Benoit
mesh_terms: D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation / Q000235:genetics*; D054278:Embryonal Carcinoma Stem Cells; D005786:Gene Expression Regulation; D016678:Genome; D051379:Mice; D059372:Nucleotide Motifs; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D020218:Response Elements; D047488:Retinoid X Receptors / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin