MCB Accepts, published online ahead of print on 2 November 2009

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Mol. Cell. Biol. doi:10.1128/MCB.00756-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Cell-specific interaction of retinoic acid receptors with target genes in mouse embryonic fibroblasts and embryonic stem cells.

Laurence Delacroix, Emmanuel Moutier, Gioia Altobelli, Stephanie Legras, Olivier Poch, Mohamed-Amin Choukrallah, Isabelle Bertin, Bernard Jost, and Irwin Davidson^*

Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/UDS, 1 Rue Laurent Fries, 67404 Illkirch Cédex, France; Immunologie et Maladies Infectieuses, GIGA +2, Bat B34, 1 ave. de l'Hôpital, 4000 Liège – Belgique; Ecole Supérieur de Biotechnologie de Strasbourg, Pole API, 67400 Illkirch France

^* To whom correspondence should be addressed. Email: irwin{at}titus.u-strasbg.fr.

All trans-retinoic acid (RA) induces transforming growth factor beta (TGF)-dependent autocrine growth of mouse embryonic fibroblasts (MEFs). We have used chromatin immunoprecipitation to map 354 RA receptor (RAR) binding loci in mouse embryonic fibroblasts MEFs most of which were similarly occupied by the RAR and RAR receptors. Only a subset of the genes associated with these loci are regulated by RA, amongst which are several critical components of the TGF pathway. We also show RAR binding to a novel series of target genes involved in cell cycle regulation, transformation and metastasis suggesting new pathways by which RA may regulate proliferation and cancer. Few of the RAR binding loci contained consensus direct repeat (DR) type elements. The majority comprised either degenerate DRs or no identifiable DRs, but anomalously-spaced half sites. Furthermore, we identify 462 RAR target loci in embryonic stem (ES) cells and show that their occupancy is cell-type specific. Our results also show that differences in the chromatin landscape regulate accessibility of RARs to a subset of more than 700 identified loci thus modulating the repertoire of target genes that can be regulated and the biological effects of RA.