HisTrader identifies nucleosome-free regions within ChIP-based profiling of histone post-translational modifications

Enhancers and promoters regulate cell identity through the binding of transcription factors (TFs) to specific DNA motifs within accessible chromatin. These regulatory regions are often identified using chromatin immunoprecipitation (ChIP)-based assays targeting histone modifications, such as ChIP sequencing (ChIP-seq), HiChIP, and proximity-ligation-assisted ChIP-seq (PLAC-seq). However, the large size of the enriched regions, or peaks, can make it difficult to pinpoint the precise DNA sequence where TFs act or where trait- or disease-associated variants exert their effects. We present HisTrader, a computational approach that identifies nucleosome-free regions (NFRs) within ChIP-based profiling of histone modification peaks, which reduces the target sequence length for motif discovery and genetic variant prioritization. By focusing on TF accessible sites, HisTrader improves motif-based detection of the regulatory mechanisms linking cellular transitions and disease states. In addition, HisTrader enables more accurate characterization of regulatory elements affected by genetic variation contributing to disease.