Transcription factors (TFs) play central roles in maintaining “stemness” of ES cells and their differentiation into several hundreds of adult cell types. Their regulatory competence is routinely assessed by detecting target genes to which they bind. However, these data do not indicate which target genes are activated, repressed, or not affected by the change of TF abundance. There is a lack of large-scale studies that compare the genome binding of TFs with the expression change of target genes after manipulation of each TF.
In this paper we associated human TFs with their target genes by two criteria: binding to genes, evaluated from published ChIP-seq data (n = 1891); and change of target gene expression shortly after induction of each TF in human ES cells. Lists of direction- and strength-specific regulated target genes are generated for 319 TFs with expected proportion of false positives ≤0.30, including 64 new TFs not present in four existing databases of target genes. Our lists of direction-specific targets for 182 TFs are larger that in the TRRUST database. In average, 32.8% of genes that respond ≥2 fold to the induction of TFs are regulated targets. Regulated target genes indicate that the majority of TFs are either strong activators or strong repressors, whereas sets of genes that responded ≥2 fold to the induction of TFs did not show strong asymmetry in the direction of expression change. The majority of human TFs (80.2%) regulated their target genes primarily via binding to enhancers. Repression of target genes is more often mediated by promoter-binding than activation of target genes. Enhancer-36 promoter loops are more abundant among strong activator and repressor TFs.
We developed an Atlas of Regulated Targets of TFs (ART-TF) in human ES cells by combining data on TF binding with data on gene expression change after manipulation of individual TFs. Sets of regulated gene targets were identified with a controlled rate of false positives. This approach contributes to the understanding of biological functions of TFs and organization of gene regulatory networks. This atlas should be a valuable resource for ES cell-based regenerative medicine studies.