Local DNA shape is a general principle of transcription factor binding specificity in Arabidopsis thaliana

Abstract

Understanding gene expression will require understanding where regulatory factors bind genomic DNA. The frequently used sequence-based motifs of protein-DNA binding are not predictive, since a genome contains many more binding sites than are actually bound and transcription factors of the same family share similar DNA-binding motifs. Traditionally, these motifs only depict sequence but neglect DNA shape. Since shape may contribute non-linearly and combinational to binding, machine learning approaches ought to be able to better predict transcription factor binding. Here we show that a random forest machine learning approach, which incorporates the 3D-shape of DNA, enhances binding prediction for all 216 tested Arabidopsis thaliana transcription factors and improves the resolution of differential binding by transcription factor family members which share the same binding motif. We observed that DNA shape features were individually weighted for each transcription factor, even if they shared the same binding sequence.

Double DAP-seq uncovered synergistic DNA binding of interacting bZIP transcription factors

“…For plant bZIPs, the sequences flanking the ACGT elements have been extensively investigated for their role in determining DNA binding activity 23 , 112 . Recent analyses of published DAP-seq data, focused on the core ACGT motif, showed that the flanking sequences were insufficient to determine binding 112 and that DNA shape surrounding the core motif contributed to differential binding by family members 113 . For human bZIPs, PBM experiments found that DNA binding specificities of the heterodimers were grouped into three major classes in relation to the homodimer binding sites: juxtaposing homodimer half-sites, overlapping homodimer half-sites, and emergent sites not readily inferred from the homodimer half-sites 11 .…”

Uncovering the “ZIP code” for bZIP dimers reveals novel motifs, regulatory rules and one billion years of cis-element evolution

“…For plant bZIPs, the sequences flanking the ACGT elements have been extensively investigated for their role in determining DNA binding activity 22,84 . Recent analyses of published DAP-seq data, focused on the core ACGT motif, showed the flanking sequences were insufficient to determine binding 84 and DNA shape surrounding the core motif contributed to differential binding by family members 85 . For human bZIPs, PBM experiments found that DNA binding specificities of the heterodimers were grouped into three major classes in relation to the homodimer binding sites: juxtaposing homodimer half-sites, overlapping homodimer half-sites, and emergent sites not readily inferred from the homodimer half-sites 11 .…”

Predictions of DNA mechanical properties at a genomic scale reveal potentially new functional roles of DNA-flexibility

“…The flanking regions of motifs, while less conserved, play an important role in TF motif recognition and binding (51). Recently, this has been linked to the shape and flexibility of these regions (17,18).…”

“…Both detection capabilities of proteins for specific shape properties of DNA as well as bending of the DNA upon protein binding have been reported (13)(14)(15), reviewed in (16). A recent publication succeeded in predicting DNA-protein interaction by explicitly considering DNA shape as a determinant feature (17). A puzzling observation with regard to TF-binding to genomic regions has been that some loci with canonical TF-binding motifs present were found to be bound by TFs, while others were not.…”