Evolution of the repertoire of nuclear receptor binding sites in genomes

Nuclear receptors (NRs) are ligand-dependent transcription factors with important roles in normal development and physiology and in a wide array of pathologies. While identification of natural or synthetic ligands for all human NRs has clarified their physiological roles and led to numerous therapeutic applications, much remains to be understood about the mechanisms by which NRs control transcription of specific networks of target genes. The DNA binding domain, composed of two C4 type zinc fingers, is the most conserved region in NRs. Binding motif selectivity stems from variations in dimerization interfaces in the DNA and ligand binding domains as well as from divergence in a few base-contacting residues in the first zinc finger. However, overlaps in DNA binding patterns suggest competition between different NRs at target sites in vivo, resulting in cross-regulation of subsets of target gene networks. As NRs can regulate transcription even when bound far from the transcription initiation sites of target genes, the considerable expansion in intergenic DNA in genomes throughout evolution likely contributes to the diversity and complexity of tissue-specific gene regulation by NRs. In particular, the presence of NR binding sites in the primate-specific Alu family of short-interspersed elements has been shown to confer transcriptional regulation by NRs to adjacent genes, although the impact on NR regulatory networks at the genome-wide scale remains to be more fully evaluated.