Corepressors of agonist-bound nuclear receptors

Abstract

Nuclear receptors (NRs) rely on coregulator proteins to modulate transcription of target genes. NR coregulators can be broadly subdivided into coactivators which potentiate transcription and corepressors which silence gene expression. The prevailing view of coregulator action holds that in the absence of agonist the receptor interacts with a corepressor via the corepressor nuclear receptor (CoRNR, "corner") box motifs within the corepressor. Upon agonist binding, a conformational change in the receptor causes the shedding of corepressor and the binding of a coactivator which interacts with the receptor via NR boxes within the coregulator. This view was challenged with the discovery of RIP140 which acts as a NR corepressor in the presence of agonist and utilizes NR boxes. Since then a number of other corepressors of agonist-bound NRs have been discovered. Among them are LCoR, PRAME, REA, MTA1, NSD1, and COPR1 Although they exhibit a great diversity of structure, mechanism of repression and pathophysiological function, these corepressors frequently have one or more NR boxes and often recruit histone deacetylases to exert their repressive effects. This review highlights these more recently discovered corepressors and addresses their potential functions in transcription regulation, disease pharmacologic responses and xenobiotic metabolism.

Figure 1

Models for corepressor and coactivator regulation of nuclear receptors. Note: for simplicity, only one of the two receptor dimers is illustrated. A) Corepressors interacting with NR in the absence of ligand. Their interaction with chromatin modifiers, e.g., HDACs leads to histone states unfavorable for transcription and expression of target gene is blocked. B) Coactivators interacting with NR in the presence of agonist. Agonist occupation of the NR ligand binding domain (LBD) leads to exchange of corepressors for coactivators, and in this scenario, recruitment of chromatin modifiers e.g., histone acetyl transferases (HAT) which acetylate lysine side chains. The remodeled, open chromatin structure allows addition proteins positively regulating transcription (not shown) to be recruited and promoter activity to ensue. C) Agonist-dependent corepression. REA competes with SRC for the AF-2 of ligand-bound receptor reducing the opportunity for transcription-enhancing proteins, e.g., HAT, to participate in the transcription complex. Further loss of transcription-favorable chromatin structure may be lost by REA’s direct association with HDACs and subsequent reduction of acetylated histones. D) Generalized version of agonist-dependent corepression. Transcriptional repressors in addition to or instead of HDACs may participate in blocking expression. AF-1: activating function 1. AF-2: activating function 2. DBD: DNA binding domain of NR. Lig: ligand. Ac: acetylated residues on histones comprising nucleosome. CoAct: coactivator. HAT: histone acetyl transferase. Other abbreviations defined in text.