title: Feed-forward transcriptional programming by nuclear receptors: regulatory principles and therapeutic implications.
abstract: Nuclear receptors (NRs) are widely targeted to treat a range of human diseases. Feed-forward loops are an ancient mechanism through which single cell organisms organize transcriptional programming and modulate gene expression dynamics, but they have not been systematically studied as a regulatory paradigm for NR-mediated transcriptional responses. Here, we provide an overview of the basic properties of feed-forward loops as predicted by mathematical models and validated experimentally in single cell organisms. We review existing evidence implicating feed-forward loops as important in controlling clinically relevant transcriptional responses to estrogens, progestins, and glucocorticoids, among other NR ligands. We propose that feed-forward transcriptional circuits are a major mechanism through which NRs integrate signals, exert temporal control over gene regulation, and compartmentalize client transcriptomes into discrete subunits. Implications for the design and function of novel selective NR ligands are discussed.
authors.affiliation: Department of Medicine, National Jewish Health, Denver, CO, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Sasse
authors.affiliation: Department of Medicine, National Jewish Health, Denver, CO, USA; Department of Medicine, University of Colorado, Denver, CO, USA. Electronic address: gerbera@njhealth.org.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Gerber
mesh_terms: D000818:Animals; D053263:Gene Regulatory Networks; D006801:Humans; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear
keywords: Estrogen; Feed forward; Glucocorticoid; Nuclear receptor; Selective ligand