A major challenge is to link enhancers to their target genes21,22. Uniquely, FANTOM5 CAGE allows for direct comparison between transcriptional activity of the enhancer and of putative target gene TSSs across a diverse set ofhuman cells. Based on pair-wise expression correlation, nearly half (40%) of the inferred TSS-associated enhancers (Methods) were linked with the nearest TSS, and 64% of enhancers have at least one correlated TSS within 500kb. Several (10,260, 15.3%) associations are supported by ChIA-PET (RNAPII-mediated) interaction data21, and the supported fraction increases with the correlation threshold (Supplementary Fig. 29a). The fraction of supported associations is 4.8-fold higher than that of associations predicted from DNase hypersensitivity correlations10 (20.6% vs. 4.3%, at the same correlation threshold), indicating that transcription is a better predictor of regulatory targets than chromatin accessibility. Conserved sequence motifs and ChIP-seq peaks also co-occurred significantly in associated enhancer-promoter pairs (Benjami-Hochberg FDR<0.05, binomial test), suggesting an additive or synergistic cooperation between enhancers and promoters at RNAPII foci.
