combined with massively parallel DNA sequencing (ChIP-seq) and the profiling of DNase I hypersensitive sites (DHSs)) [20-22]. Two major themes emerged from these studies. First, loci with signature enhancer features (DHSs, H3K4me1, H3K27ac) are highly enriched for genetic risk variants relative to other chromatin-defined elements such as promoters and insulators [21]. Second, risk variants preferentially map to enhancers specific to disease-relevant cell types in both cancer and other common diseases [21]. For example, type 2 diabetes-associated variants preferentially map to pancreatic islet enhancers [22-25], and SNPs predisposing to colon cancer are enriched in enhancer elements in colon cancer cells and colon crypts, from which colon cancer is derived [26]. Further assessment of the effects of enhancer risk variants has shown that they can alter transcription-factor-binding sites (TFBSs) and impact the affinity of transcription factors for chromatin, and/or induce allele-specific effects on target gene expression [6,27-40]. These studies illustrate the utility of epigenomic profiling for identifying risk variants that lie in putative enhancer elements and for identifying disease-relevant cell types in which the enhancer variants could exert their regulatory effects.
