Enhancing enhancers: new complexities in the retinoid regulation of gene expression.

Retinoic acid is a signalling molecule central to morphogenesis and musculoskeletal development. It can exist in several isomeric forms, of which all-trans- and 9-cis-retinoic acid are thought to be the most relevant as signalling molecules. Retinoic acid regulates gene expression via RARs (retinoic acid receptors) working as heterodimers with RXRs (retinoid X receptors). RXRs also heterodimerize with other nuclear receptors. In this issue of the Biochemical Journal, Harris et al. have shown that an enhancer responsible for chondrocyte-specific expression of the col11a2 gene is itself regulated by a retinoic-acid-dependent interaction with RXRbeta bound to a downstream response element. Thus, RXRs bound to hormone-response elements can regulate gene expression indirectly via interactions with tissue-specific enhancers. This study raises interesting questions about the nature of the response element, the RXRbeta partner and the ligands able to influence col11a2 expression, and will provide a model system with which to understand tissue and ligand specificity of retinoid responses.