  We use nucleosome maps obtained by high-throughput sequencing to study
sequence specificity of intrinsic histone-DNA interactions. In contrast with
previous approaches, we employ an analogy between a classical one-dimensional
fluid of finite-size particles in an arbitrary external potential and arrays of
DNA-bound histone octamers. We derive an analytical solution to infer free
energies of nucleosome formation directly from nucleosome occupancies measured
in high-throughput experiments. The sequence-specific part of free energies is
then captured by fitting them to a sum of energies assigned to individual
nucleotide motifs. We have developed hierarchical models of increasing
complexity and spatial resolution, establishing that nucleosome occupancies can
be explained by systematic differences in mono- and dinucleotide content
between nucleosomal and linker DNA sequences, with periodic dinucleotide
distributions and longer sequence motifs playing a secondary role. Furthermore,
similar sequence signatures are exhibited by control experiments in which
genomic DNA is either sonicated or digested with micrococcal nuclease in the
absence of nucleosomes, making it possible that current predictions based on
high-throughput nucleosome positioning maps are biased by experimental
artifacts.
