Genome-wide transcription factor activities are explained by intrinsic conformational dynamics of binding-sites and distal flanking-regions

Abstract

Transcription factors (TFs) recognize small DNA sequence motifs directly or through their sequence-dependent structure. While sequence composition and degeneracy are verified to be the defining factors of TF binding specificity, the role of conformational dynamics of the DNA remains poorly understood. With growing evidence from next generation sequencing (NGS) data suggesting the inadequacy of sequence-only models, alternative models for describing the TF binding preferences are required, wherein the conformational dynamics presents an attractive option. Here, we report a novel method (DynaSeq) which accurately predicts DNA-conformational ensembles for genomic targets of TFs. Using DynaSeq we demonstrate how the dynamics of binding sites and their distal flanking regions can be used to elucidate TF-binding patterns for two model systems: cell type-specific binding of STAT3 and chromatin structural specificity of 3 functional TF classes viz. pioneers, settlers and migrants. We find that TF preferences in both these systems can be accurately explained by the conformational dynamics of their binding sites and their distal flanking DNA regions. Conformational dynamics not only distinguishes binding sites from genomic backgrounds in STAT3; it also points to a modular organization of their surrounding regions. Further, the differential binding modes of STAT3-DNA reveal a potential mechanism of cellular specificity. Our model identifies clear signatures to accurately classify pioneer, migrant and settler TF targets from the dynamics of distal flanking regions. This suggests that the chromatin preferences of TFs are significantly influenced by the intrinsic conformational dynamics of the DNA surrounding the TF binding sites.