Role of Intrinsically Disordered Regions in Transcription Factor Binding Specificity

Recent experiments have shown that the yeast eukaryotic transcription factor (TF) Msn2 has an intrinsically disordered region (IDR) important for binding specificity, the ability to discriminate between the functional and non-functional binding sites on the DNA. How the IDR accomplishes this is unknown. One clue is in the fact that Msn2 promoter binding sites are enriched in sequences that tend to be in the A-DNA conformation. A-DNA, compared to the typical B-DNA observed in solution, is a fatter, and it minor grooves have an increased propensity to interact with hydrophobic residues. Hydrophobic residues were observed to be the most important residues for Msn2’s IDR to aid with binding specificity. We hypothesize that Msn2’s IDR recognizes these A-DNA sequences in Msn2 promoters to increase binding specificity. To explore this hypothesis, we develop statistical mechanics models of the Monod-Wyman-Changeux variety, which can account for this A-DNA recognition by the IDR. We perform sensitivity analysis to determine the parameter regimes where the models predict that TF binding specificity is sensitive to DNA conformation. We also fit our models to data from Chromatin Endogenous Cleavage sequencing (ChEC-seq) performed on different Msn2 constructs (full TF and IDR-only) to test their validity. This theoretical study provides ideas for future experiments to unravel the functional role of IDRs in eukaryotic TFs.