Abstract:

Despite significant progress in annotating the genome with experimental methods, much of the regulatory noncoding genome remains poorly defined. Here we assert that regulatory elements may be characterized by leveraging local epigenomic signatures at sites where specific transcription factors (TFs) are bound. To link these two identifying features, we introduce IMPACT, a genome annotation strategy which identifies regulatory elements defined by cell-state-specific TF binding profiles, learned from 515 chromatin and sequence annotations. We validate IMPACT using multiple compelling applications. First, IMPACT predicts TF motif binding with high accuracy (average AUC 0.92, s.e. 0.03; across 8 TFs), a significant improvement (all p<6.9e-15) over intersecting motifs with open chromatin (average AUC 0.66, s.e. 0.11). Second, an IMPACT annotation trained on RNA polymerase II is more enriched for peripheral blood cis-eQTL variation (N=3,754) than sequence based annotations, such as promoters and regions around the TSS, (permutation p<1e-3, 25% average increase in enrichment). Third, integration with rheumatoid arthritis (RA) summary statistics from European (N=38,242) and East Asian (N=22,515) populations revealed that the top 5% of CD4+ Treg IMPACT regulatory elements capture 85.7% (s.e. 19.4%) of RA h2 (p<1.6e-5) and that the top 9.8% of Treg IMPACT regulatory elements, consisting of all SNPs with a non-zero annotation value, capture 97.3% (s.e. 18.2%) of RA h2 (p<7.6e-7), the most comprehensive explanation for RA h2 to date. In comparison, the average RA h2 captured by compared CD4+ T histone marks is 42.3% and by CD4+ T specifically expressed gene sets is 36.4%. Finally, integration with RA fine-mapping data (N=27,345) revealed a significant enrichment (2.87, p<8.6e-3) of putatively causal variants across 20 RA associated loci in the top 1% of CD4+ Treg IMPACT regulatory regions. Overall, we find that IMPACT generalizes well to other cell types in identifying complex trait associated regulatory elements.