A new set of combinatorial dimeric codes for nuclear hormone receptor–target gene specificity

In vertebrates and invertebrates, nuclear hormone receptors (NRs) recognize a consensus DNA element of AGGTCA in the promoters of target genes through a highly conserved 10 amino acid motif called the P-box. AGGTCA is arrayed as dimeric repeats with certain combinations of orientation and spacing, conferring binding and transcription specificities to cognate NR homo- or heterodimers. However, the combinations are fewer than NR dimers and may not explain all NR-target gene specificities. Here in Caenorhabditis elegans, we identify a response element 79/49RE for two HNF4α NRs: NHR-79 and NHR-49. 79/49RE is two repeats of GACTAC inverted and spaced by 3 bp (IR3). NHR-49's P-box is highly conserved while NHR-79's diverges in four amino acids; nonetheless, NHR-49 and NHR-79 each alone can bind IR3 but together bind IR3 preferably as a heterodimer. Upon fasting, NHR-79-NHR-49-79/49RE upregulates genes for peroxisome proliferation, peroxisomal β-oxidation, and lipid droplet catabolism. Moreover, direct, inverted, and everted repeats of GACTAC spaced by 0-6 bp are widespread in genes of other functional categories, some of which are uniquely regulated by NHR-49. Thus, the P-box motif is remarkably plastic to recognize the novel repeat, which constitutes a new set of combinatorial dimeric codes for NR-target gene specificities.