  The notion that transcription factors bind DNA only through specific,
consensus binding sites has been recently questioned. In a pioneering study by
Pugh and Venters no specific consensus motif for the positioning of the human
pre-initiation 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 non-random,
statistical pattern of repetitive nucleotide triplets that correlates with the
genome-wide binding preferences of PIC measured by Chip-exo. We analyze the
triplet enrichment and depletion near the transcription start site (TSS) and
identify triplets that have the strongest effect on PIC-DNA nonconsensus
binding. Our results constitute a proof-of-concept for a new design principle
for protein-DNA recognition in the human genome, which can lead to a better
mechanistic understanding of transcriptional regulation.
