RoboCOP: Jointly computing chromatin occupancy profiles for numerous factors from chromatin accessibility data

Abstract

Chromatin is the tightly packaged structure of DNA and protein within the nucleus of a cell. The arrangement of different protein complexes along the DNA modulates and is modulated by gene expression. Measuring the binding locations and level of occupancy of different transcription factors (TFs) and nucleosomes is therefore crucial to understanding gene regulation. Antibody-based methods for assaying chromatin occupancy are capable of identifying the binding sites of specific DNA binding factors, but only one factor at a time. On the other hand, epigenomic accessibility data like ATAC-seq, DNase-seq, and MNase-seq provide insight into the chromatin landscape of all factors bound along the genome, but with minimal insight into the identities of those factors. Here, we present RoboCOP, a multivariate state space model that integrates chromatin information from epigenomic accessibility data with nucleotide sequence to compute genome-wide probabilistic scores of nucleosome and TF occupancy, for hundreds of different factors at once. We apply RoboCOP to MNase-seq data to elucidate the protein-binding landscape of nucleosomes and 150 TFs across the yeast genome. Using available protein-binding datasets from the literature, we show that our model predicts the binding of these factors genome-wide more accurately than existing methods.