Spatially resolved profiling and Footprint Analysis of the Steroid Nuclear Receptors Reveals a Role for the Disordered N-Terminal Domains in Genome Targeting and AP-1 Interaction

Transcription factors (TFs) regulate gene expression by binding to cis-regulatory regions within vast genomes. In budding yeast, intrinsically disordered regions (IDRs) emerged as key effectors of genome preferences, but whether this holds in the complex mammalian genomes remains unclear. Mammalian TFs are enriched with long IDRs, exemplified by the disordered N-terminal domains (NTDs) of the nuclear steroid receptors (SRs). Here, by comparing genomic locations of three SRs and their truncation mutants, we show that the NTDs direct the selection of SR target sites. Footprint analysis revealed that SR mutants lacking the NTD become dependent on the AP-1 motif and further suggest that the NTD can direct genome recognition independent of co-binding TFs, which we confirmed by testing SR binding across the budding yeast genome. Our results suggest that IDRs assist in defining the TF binding targets, opening new avenues for modulating activities of therapeutically relevant TFs.