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.

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 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, among 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 the accessibility of a subset of more than 700 identified loci to RARs, thus modulating the repertoire of target genes that can be regulated and the biological effects of RA.