Genome-wide determinants of sequence-specific DNA binding. (A) Formaldehyde cross-linking (XL) efficiency is influenced by the fortuitous occurrence of G/C in the vicinity of lysine (Lys) side chains of the protein that interact with DNA. (B) GRF binding is specified by a combination of DNA sequence and shape readout. (C) Functional GRF binding sites having proper sequence and shape typically reside in promoters. Weaker sites may exist outside of promoters but are rendered inaccessible by chromatin. Strong consensus motifs that lack proper shape features do not bind GRFs and so may arise anywhere in the genome without consequence.