Dissecting the retinoid-induced differentiation of F9 embryonal stem cells by integrative genomics.
Fiche publication
Date publication
janvier 2011
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GRONEMEYER Hinrich
Tous les auteurs :
Mendoza-Parra MA, Walia M, Sankar M, Gronemeyer H
Lien Pubmed
Résumé
Retinoic acid (RA) triggers physiological processes by activating heterodimeric transcription factors (TFs) comprising retinoic acid receptor (RARalpha, beta, gamma) and retinoid X receptor (RXRalpha, beta, gamma). How a single signal induces highly complex temporally controlled networks that ultimately orchestrate physiological processes is unclear. Using an RA-inducible differentiation model, we defined the temporal changes in the genome-wide binding patterns of RARgamma and RXRalpha and correlated them with transcription regulation. Unexpectedly, both receptors displayed a highly dynamic binding, with different RXRalpha heterodimers targeting identical loci. Comparison of RARgamma and RXRalpha co-binding at RA-regulated genes identified putative RXRalpha-RARgamma target genes that were validated with subtype-selective agonists. Gene-regulatory decisions during differentiation were inferred from TF-target gene information and temporal gene expression. This analysis revealed six distinct co-expression paths of which RXRalpha-RARgamma is associated with transcription activation, while Sox2 and Egr1 were predicted to regulate repression. Finally, RXRalpha-RARgamma regulatory networks were reconstructed through integration of functional co-citations. Our analysis provides a dynamic view of RA signalling during cell differentiation, reveals RAR heterodimer dynamics and promiscuity, and predicts decisions that diversify the RA signal into distinct gene-regulatory programs.
Référence
Mol Syst Biol. 2011 Oct 11;7:538