How transcription factors (TFs) bind rapidly at specific sites within large genomes remains a major mystery. Specificity is puzzling since TFs select a small fraction of their potential binding sites - short and highly abundant DNA motifs. Rapid detection of these selected sites is challenging due to the small motif size and the large number of non-specific sites within a genome. Despite extensive efforts, a unifying model accounting for these challenges, underlying the foundations of gene regulation, is still missing.
Our recent results revealed an unexpected role of long intrinsically disordered regions (IDRs) in determining the in-vivo binding specificity of TFs. Long IDRs are ubiquitous among eukaryotic TFs, but their potential role is largely unknown. By studying two budding yeast TFs, we found that in-vivo binding specificity depends on long (>500 residues) IDRs located outside the DNA binding domains (DBDs). Furthermore, IDRs direct TF binding to the selected set of promoters using multiple weak specificity determinants distributed throughout their entire sequence.
Our results suggest that TFs search for their binding sites through a two-tier process: Specificity determinants distributed within long IDRs direct TFs to broad promoter regions, allowing for subsequent localized search of the DBD for its short binding motif. We plan to establish this model by: (1) Defining the molecular basis of IDR-promoter recognition and its sequence recognition code, (2) Defining the dynamic profile of IDR-based DNA recognition, and (3) Elucidating the evolutionary implications of this novel recognition mode.
Through a combination of experiments, computation and theory, carried out by an interdisciplinary group of students, our study will establish a new paradigm that explains the efficiency and specificity of the search of TFs for their in-vivo binding targets, providing a new solution for a long-standing mystery.
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