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Nuclear receptors (NRs) comprise a large family of signal dependent transcription factors that respond to a diverse range of fat soluble ligands including steroids, vitamins A and D, long chain fatty acids, bile acids, thyroid hormone and xenobiotic toxins. Through their cognate receptors, nuclear-active hormones orchestrate a multiplicity of biological functions from embryonic development to endocrine physiology, pathology, and therapeutics. Since the cloning of the human glucocorticoid receptor (hGR) in 1985 and the estrogen receptor (ER) in 1986 this family has grown to include 48 unique receptors integrally linked to the evolution of the entire animal kingdom. Intense research efforts have been dedicated to understanding the molecular mechanism of nuclear hormone signaling and how receptor interactions with the genome influence basic biology. At a structural level, NR-mediated transcriptional activation is a complex, multistep process orchestrated primarily by the concerted actions of a DNA binding domain (DBD) and a ligand binding domain (LBD) incorporating coregulator binding sites. While initial structural studies on isolated domains provided a fundamental understanding of the discrete functions of these domains, a fully integrated picture on how NRs are dynamically regulated to enact a coordinated gene transcription response was lacking. Newly emerging crystal structures, reviewed by Fraydoon Rastinejad, are now shedding light on the quaternary arrangement of NR protein complexes, with direct implications for drug discovery and design (Rastinejad et al. 2013). Concurrently, tremendous advances in structural studies of coregulator proteins, reviewed by John Schwabe, are revealing how NRs orchestrate protein complexes that modify chromatin to activate or repress gene transcription (Millard et al. 2013). These reviews detail the major advances in our understanding of the molecular mechanisms of nuclear receptor action achieved through structural studies. However, for many decades, studies of NR action at the chromatin level were limited to promoters of wellcharacterized target genes. Perhaps one of the foremost questions of nuclear receptor biology has been how a single hormone responsive transcription factor, reading the same DNA template, is capable of regulating different genes in different cell types. Recent advances in high content DNA sequencing technology have revolutionized the study of NR signaling, allowing interrogation of DNA bound sites on a genome-wide scale. Focusing on the macrophage, Christopher Glass explains how whole genome sequencing has revealed how modifications of the epigenetic landscape driven by lineage determining factors dictate NR binding sites and thereby target genes (Zhang & Glass 2013). Furthermore, untargeted sequencing approaches have revealed that the majority of NR binding sites are located not in promoter regions but in interand intra-genic locations that exhibit features of enhancers. Many of these enhancer sites appear to be functional, as evidenced by the production of enhancertemplated non-coding RNA (eRNA). This area is rapidly evolving and fundamentally changing our view of how NRs signal at the chromatin level. Consistent with the importance of NR signaling on whole body metabolic homeostasis, endogenous ligand production and degradation must be tightly regulated. However, in the setting of metabolic disease such as obesity, disruption of NR ligand levels can lead to dysregulated NR signaling that contributes to and augments the severity of the disease. Evan Simpson reviews how chronic inflammation associated with high fat diet

Journal of Molecular Endocrinology 25th anniversary special issue