Regulatory Elements in Noncoding DNA in the Chromosome 9p21 Locus

1. Harismendy O, Notani D, Song X, Rahim NG, Tanasa B, Heintzman N, Ren B, Fu XD, Topol EJ, Rosenfeld MG, Frazer KA. 9p21 DNA variants associated with coronary artery disease impair interferon-g signalling response . Nature. 2011;470(7333):264–268. PMID: 21307941. Study HypothesisA novel locus on chromosome 9p21 has been identified in numerous genome-wide association studies as the most highly associated with coronary artery disease (CAD) and myocardial infarction. Understanding the mechanism by which the locus influences disease has been a challenge because the locus lies entirely within noncoding DNA—in a so-called “gene desert” at a long distance from the closest genes. The authors hypothesized that common DNA variants in the locus alter transcriptional regulatory elements that engage in long-range interactions with and modulate expression of genes outside of the locus.1 How Was the Hypothesis Tested?The authors integrated multiple data sets to identify potential transcriptional regulatory elements in the 9p21 CAD locus. They searched in various types of human cells for chromatin modification “marks” of 3 types—promoters marked by enrichment of histone H3 trimethylated at lysine 4 (H3K4me3); insulators marked by CTCF-binding sites; and enhancers marked by enrichment of histone H3 monomethylated at lysine 4 (H3K4me1), or p300- and MED1-binding sites, or presence of DNase hypersensitivity sites. They …