(A) Ligand-dependent transactivation. The binding of hormones or synthetic agonists causes the recruitment of coactivator complexes to the ligand-binding domain. Ligand-dependent recruitment of these factors is similar for heterodimeric receptors and steroid hormone receptors (not shown). For simplicity, only a single generic complex is illustrated. In general, ligand-dependent transcription of nuclear receptor target genes is associated with the recruitment of numerous coactivator complexes that act in a combinatorial or sequential manner. These complexes are associated with a number of enzymatic activities, including histone acetyltransferase (HAT), histone methyltransferase (HMT), and nucleosome remodeling (NRM) activities. Structurally distinct ligands may alter the pattern of recruitment of these factors, resulting in altered patterns of gene activation. (B) Active repression. A subset of heterodimeric nuclear receptors, including PPAR/RXR and LXR/RXR heterodimers, are capable of binding to REs in the absence of ligand and recruiting corepressor complexes that actively repress transcription. A number of corepressor complexes are associated with histone deacetylase (HDAC) activities, as well as histone methyltransferase and nucleosome remodeling activities that are generally distinct from those associated with coactivator complexes. HDM, histone demethylase. (C) SERM/antagonist–dependent repression. Some SERMs (shown here in gray), such as tamoxifen, and PPAR antagonists promote corepressor interactions with the ligand-binding domain, resulting in active repression in permissive cell types. (D) Ligand-dependent trans-repression. Many nuclear receptors, including glucocorticoid receptors, ERs, PPARs, and LXRs (indicated in blue), are capable of antagonizing signal-dependent activation of inflammatory response genes by transcription factors such as NF-κB.