Specifying cellular context of transcription factor regulons for exploring context-specific gene regulation programs

Understanding the role of transcription and transcription factors in cellular identity and disease, such as cancer and autoimmunity, is essential. However, comprehensive data resources for cell line-specific transcription factor-to-target gene annotations are currently limited. To address this, we developed a straightforward method to define regulons that capture the cell-specific aspects of TF binding and transcript expression levels. By integrating cellular transcriptome and transcription factor binding data, we generated regulons for four common cell lines comprising both proximal and distal cell line-specific regulatory events. Through systematic benchmarking involving transcription factor knockout experiments, we demonstrated performance on par with state-of-the-art methods, with our method being easily applicable to other cell types of interest. We present case studies using three cancer single-cell datasets to showcase the utility of these cell-type-specific regulons in exploring transcriptional dysregulation. In summary, this study provides a valuable tool and a resource for systematically exploring cell line-specific transcriptional regulations, emphasizing the utility of network analysis in deciphering disease mechanisms.