Automated mapping of large-scale chromatin structure in ENCODE

Motivation: A recently developed DNasel assay has given us our first genome-wide view of chromatin structure. In addition to cataloging DNasel hypersensitive sites, these data allows us to more completely characterize overall features of chromatin accessibility. We employed a Bayesian hierarchical change-point model (CPM), a generalization of a hidden Markov Model (HMM), to characterize tiled microarray DNasel sensitivity data available from the ENCODE project. Results: Our analysis shows that the accessibility of chromatin to cleavage by DNasel is well described by a four state model of local segments with each state described by a continuous mixture of Gaussian variables. The CPM produces a better fit to the observed data than the HMM. The large posterior probability for the four-state CPM suggests that the data falls naturally into four classes of regions, which we call major and minor DNasel hypersensitive sites (DHSs), regions of intermediate sensitivity, and insensitive regions. These classes agree well with a model of chromatin in which local disruptions (DHSs) are concentrated within larger domains of intermediate sensitivity, the accessibility islands. The CPM assigns 92 of the bases within the ENCODE regions to the insensitive regions. The 5.8 of the bases that are in regions of intermediate sensitivity are clearly enriched in functional elements, including genes and activating histone modifications, while the remaining 2.2 of the bases in hypersensitive regions are very strongly enriched in these elements.