Integrative analysis of transcription factor occupancy at enhancers and disease risk loci in noncoding genomic regions

Abstract

ABSTRACTNoncoding regions of the human genome possess enhancer activity and harbor risk loci for heritable diseases. Whereas the binding profiles of multiple transcription factors (TFs) have been investigated, integrative analysis with the large body of public data available so as to provide an overview of the function of such noncoding regions has remained a challenge. Here we have fully integrated public ChIP-seq and DNase-seq data (n ~ 70,000), including those for 743 human transcription factors (TFs) with 97 million binding sites, and have devised a data-mining platform —designated ChIP-Atlas—to identify significant TF-genome, TF-gene, and TF-TF interactions. Using this platform, we found that TFs enriched at macrophage or T-cell enhancers also accumulated around risk loci for autoimmune diseases, whereas those enriched at hepatocyte or macrophage enhancers were preferentially detected at loci associated with HDL-cholesterol levels. Of note, we identified “hotspots” around such risk loci that accumulated multiple TFs and are therefore candidates for causal variants. Integrative analysis of public chromatin-profiling data is thus able to identify TFs and tissues associated with heritable disorders.