Background: Retinoic acid receptors (RARs) heterodimerize with retinoid X receptors (RXRs) to regulate gene expression. Results: This heterodimer recognizes the genome via a large and diverse repertoire of direct and inverted repeat DNA elements. Conclusion:The observed diversity of binding elements changes the paradigm of how RAR-RXR recognizes the genome. Significance: Half-site spacing in the DNA binding element allosterically regulates RAR function.

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.

Background: Retinoic acid (RA) receptors regulate gene expression through binding-specific response elements (RAREs). Results: A collection of new DR5 RAREs located Ϯ10 kb from TSSs and conserved among 6 vertebrates species or more has been amassed. Conclusion:We provide a wider knowledge base for analyzing RA target genes. Significance: The RA response of the conserved target genes differs between species and tissues.