Abstract
The notion that transcription factors bind DNA only through specific, consensus binding sites has been recently questioned. No specific consensus motif for the positioning of the human preinitiation complex (PIC) has been identified. Here, we reveal that nonconsensus, statistical, DNA triplet code provides specificity for the positioning of the human PIC. In particular, we reveal a highly nonrandom, statistical pattern of repetitive nucleotide triplets that correlates with the genomewide binding preferences of PIC measured by Chip-exo. We analyze the triplet enrichment and depletion near the transcription start site and identify triplets that have the strongest effect on PIC-DNA nonconsensus binding. Using statistical mechanics, a random-binder model without fitting parameters, with genomic DNA sequence being the only input, we further validate that the nonconsensus nucleotide triplet code constitutes a key signature providing PIC binding specificity in the human genome. Our results constitute a proof-of-concept for, to our knowledge, a new design principle for protein-DNA recognition in the human genome, which can lead to a better mechanistic understanding of transcriptional regulation.