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Nucleic Acids Res. 2015 May 26;43(10):4833-54. doi: 10.1093/nar/gkv370. Epub 2015 Apr 20.

RAR/RXR binding dynamics distinguish pluripotency from differentiation associated cis-regulatory elements.

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Université de Lyon, Université Claude Bernard Lyon1, CGphiMC UMR CNRS 5534, 69622 Villeurbanne, France.
Université de Lyon, Université Claude Bernard Lyon1, LBBE UMR CNRS 5558, 69622 Villeurbanne, France.
Université d'Evry-Val d'Essonne, IBISC EA 4526, 91037 Evry, France.
IGFL, Université de Lyon, Université Lyon 1, CNRS, INRA; Ecole Normale Supérieure de Lyon, 69007 Lyon, France.
Université de Lyon, Université Claude Bernard Lyon1, CGphiMC UMR CNRS 5534, 69622 Villeurbanne, France


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.

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