Differential Regulation of the Orphan Nuclear ReceptorSmall Heterodimer Partner(SHP) Gene Promoter by Orphan Nuclear Receptor ERR Isoforms*

The orphan nuclear receptor small heterodimer partner (SHP; NR0B2) interacts with a wide array of nuclear receptors and represses their transcriptional activity. SHP expression is regulated by several other members of the nuclear receptor superfamily, including the orphan receptors SF-1 and LRH-1, and the bile acid receptor FXR. We have found that the SHPpromoter is also activated by the estrogen receptor-related receptor γ (ERRγ) but not the related ERRα and ERRβ isoforms. SHP and ERRγ mRNAs are coexpressed in several tissues, including pancreas, kidney, and heart, confirming the potential relevance of this transactivation. ERRγ transactivation is dependent on only one of five previously characterized DNA-binding sites for SF-1, and this element differs from previously reported ERR response elements. However, treatment with the histone deacetylase inhibitor trichostatin A significantly increased ERRα and ERRβ activity on this element indicating that the lack of activity of ERRα and -β may depend on their association with co-repressor in vivo. Furthermore, using protease sensitivity assays on DNA bound receptors it was demonstrated that DNA sequence of different response elements may cause allosteric modulation of ERR proteins, which in turn may be responsible for the differential activities of these receptors on different response elements. SHP inhibits ERRγ transactivation and physically interacts with all three members of ERR subfamily, as demonstrated by both yeast two-hybrid and biochemical assays. As with other SHP targets, this interaction is dependent on the AF-2 coactivator-binding site of ERRγ and the previously described N-terminal receptor interaction domain of SHP. Several recently described SHP mutations associated with moderate obesity in humans block the inhibition of ERRγ activity. Overall, these results identify a new autoregulatory loop controlling SHPgene expression and significantly extend the potential functional roles of the three ERRs.