Integrative analysis of epigenetics data identifies gene-specific regulatory elements

Understanding the complexity of transcriptional regulation is a major goal of computational biology. Because experimental linkage of regulatory sites to genes is challenging, computational methods considering epigenomics data have been proposed to create tissue-specific regulatory maps. However, we showed that these approaches are not well suited to account for the variations of the regulatory landscape between cell-types. To overcome these drawbacks, we developed a new method called SO_SCPCAPTITCHC_SCPCAPIO_SCPCAPTC_SCPCAP, that identifies and links putative regulatory sites to genes. Within SO_SCPCAPTITCHC_SCPCAPIO_SCPCAPTC_SCPCAP, we consider the chromatin accessibility signal of all samples jointly to identify regions exhibiting a signal variation related to the expression of a distinct gene. SO_SCPCAPTITCHC_SCPCAPIO_SCPCAPTC_SCPCAP outperforms previous approaches in various validation experiments and was used with a genome-wide CRISPR-Cas9 screen to prioritize novel doxorubicin-resistance genes and their associated non-coding regulatory regions. We believe that our work paves the way for a more refined understanding of transcriptional regulation at the gene-level.