Nonconsensus flanking sequence of hundreds of base pairs around in vivo binding sites: statistical beacons for transcription factor scanning

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Abstract Transcription factor (TF) binding is typically described in terms of short sequence motifs and their immediate flanking regions. However, increasing evidence suggests that broader genomic context may influence TF–DNA interactions. By a thorough analysis of the DNA sequence in the broad context ($\pm$ 5000 bp) of in vivo binding sites (as identified in a ChIP-seq or a Cut&Tag experiment), we show that the average GC content is in most cases statistically significantly increased around the binding site in a patch spanning 1000–1500 bp. This increase was observed consistently in experiment targeting the same TF in different cell lines. The surrounding of binding sites of certain TFs like MYC display a directional alteration of dinucleotide frequencies. Using sequence-derived structural descriptors, we hypothesize that DNA shape reflects (and may partly explain) patterns in sequence composition. In addition, we observe differences in sequence affinity to various potential cooperating TFs between cell lines. Altogether, we interpret these observations as indicating that the observed feature distortion reflects a coarse scanning mechanism that facilitates TF target-site recognition in absence of clear sequence sequence consensus.

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