Nuclear hormone receptors and gene expression

The nuclear hormone receptor superfamily includes receptors for thyroid and steroid hormones, retinoids and vitamin D, as well as different "orphan" r eceptors of unknown ligand. Ligands for some of these receptors have been r ecently identified, showing that products of lipid metabolism such as fatty acids, prostaglandins, or cholesterol derivatives can regulate gene expres sion by binding to nuclear receptors. Nuclear receptors act as ligand-induc ible transcription factors by directly interacting as monomers, homodimers, or heterodimers with the retinoid X receptor with DNA response elements of target genes, as well as by "cross-talking" to other signaling pathways. T he effects of nuclear receptors on transcription are mediated through recru itment of coregulators. A subset of receptors binds corepressor factors and actively represses target gene expression in the absence of ligand. Corepr essors are found within multicomponent complexes that contain histone deace tylase activity. Deacetylation leads to chromatin compactation and transcri ptional repression. Upon ligand binding, the receptors undergo a conformati onal change that allows the recruitment of multiple coactivator complexes. Some of these proteins are chromatin remodeling factors or possess histone acetylase activity, whereas others may interact directly with the basic tra nscriptional machinery. Recruitment of coactivator complexes to the target promoter causes chromatin decompactation and transcriptional activation. Th e characterization of corepressor and coactivator complexes, in concert wit h the identification of the specific interaction motifs in the receptors, h as demonstrated the existence of a general molecular mechanism by which dif ferent receptors elicit their transcriptional responses in target genes.