DNase-seq has been extensively used by the ENCODE consortium [26] and others to unveil cell-specific chromatin accessibility and its relation to differential gene expression in various cell lines [21, 77–79]. It has also been modified to study rotational positioning of individual nucleosomes [80] based on the inherent preference of DNase I to cut within the minor groove of DNA at approximately every ten bp around nucleosomes [79, 81, 82]. In addition, binding of sequence-specific regulatory factors within DHSs can affect the intensity of DNase I cleavage and generate footprints (digital genomic footprinting (DGF) or DNase I footprinting) that have been used to study TF occupancy at nucleotide resolution in a qualitative and quantitative manner [83]. DGF with deep sequencing has been implemented to uncover cell-specific TF binding motifs in humans, yielding expansive knowledge on regulatory circuits and the role of TF binding in relation to chromatin structure, gene expression, and cellular differentiation [19, 78]. Due to its high resolution, DGF has also allowed the probing of functional allele-specific signatures within DHSs [78].
