ChEA-KG: Human Transcription Factor Regulatory Network with a Knowledge Graph Interactive User Interface.

Background: Gene expression is controlled by transcription factors (TFs) that selectively bind and unbind to DNA to regulate mRNA expression of all human genes. TFs control the expression of other TFs, forming a complex gene regulatory network (GRN) with switches, feedback loops, and other regulatory motifs. Many experimental and computational methods have been developed to reconstruct the human intracellular GRN. Here we present a different approach. By submitting thousands of "up" and "down" gene sets from the RummaGEO resource for TF enrichment analysis with ChEA3, we distill signed and directed edges that connect human TFs to construct a high quality human GRN.

Results: The GRN has 131,581 signed and directed edges connecting 701 source TF nodes to 1,559 target TF nodes. The GRN is accessible via the ChEA-KG web server application, which provides interactive network visualization and analysis tools. Users may query the GRN for single or pairs of TFs or submit gene sets to perform TF enrichment analysis with ChEA3, placing the enriched TFs within the GRN. To demonstrate the utility of ChEA-KG, we extend the enrichment analysis feature to generate cell-type and cancer TF atlases. The atlases display systematically generated master regulator subnetworks of TFs for marker gene sets from 131 major normal human cell-types and 69 tumour subtypes from 10 cancers, respectively.

Conclusions: ChEA-KG is an interactive web-server application that presents to users a new method of exploring the human gene regulatory network through both network visualization and transcription factor enrichment analysis. The ChEA-KG application is available from: https://chea-kg.maayanlab.cloud/.