Date Published: February 22, 2019
Publisher: Public Library of Science
Author(s): Stephen M. Matthews, Melanie A. Eshelman, Arthur S. Berg, Walter A. Koltun, Gregory S. Yochum, Hodaka Fujii.
Crohn’s disease (CD) is a debilitating inflammatory bowel disease (IBD) that arises from chronic inflammation in the gastrointestinal tract. Genome-wide association studies (GWAS) have identified over 200 single nucleotide polymorphisms (SNPs) that are associated with a predisposition for developing IBD. For the majority, the causal variant and target genes affected are unknown. Here, we investigated the CD-associated SNP rs6651252 that maps to a gene desert region on chromosome 8. We demonstrate that rs6651252 resides within a Wnt responsive DNA enhancer element (WRE) and that the disease associated allele augments binding of the TCF7L2 transcription factor to this region. Using CRISPR/Cas9 directed gene editing and epigenetic modulation, we find that the rs6651252 enhancer regulates expression of the c-MYC proto-oncogene (MYC). Furthermore, we found MYC transcript levels are elevated in patient-derived colonic segments harboring the disease-associated allele in comparison to those containing the ancestral allele. These results suggest that Wnt/MYC signaling contributes to CD pathogenesis and that patients harboring the disease-associated allele may benefit from therapies that target MYC or MYC-regulated genes.
Crohn’s disease (CD) and ulcerative colitis (UC) are the two main classes of inflammatory bowel disease (IBD), and arise from chronic inflammation in the gastrointestinal (GI) tract . CD can present anywhere along the GI tract whereas UC is confined primarily to the colon [1,2]. In a generally accepted view, IBD results from one or more environmental triggers in a genetically susceptible individual [3,4]. While the precise environmental exposure is debatable, that fact that 5–23% of IBD patients have a first-degree relative that is also afflicted with disease is supportive of a genetic inheritance .
GWAS have identified over 200 SNPs that are associated with a predisposition for developing IBD [3,6–8]. While some of these are found within protein-coding regions of the genome, most map to intergenic and gene-poor loci . Recent work has shown that many of these non-coding SNPs are found within regions of accessible chromatin, demarcated by elevated levels of H3K27ac . Most often, these SNPs are assumed to impact the nearest gene promoter [2,3]. However, it is known that enhancers are capable of impacting more than one gene and can bypass the nearest gene to influence expression of a neighboring gene . Due to the inherent difficulty in studying non-coding regions of DNA, particularly those that may function in a cell-type specific manner, the causative impact of these non-coding SNPs on gene function largely remains a mystery. This current study focused on the CD-associated SNP, rs6651252 that maps to the 8q24 locus. This locus is a large non-coding region of the genome that contains numerous SNPs that have been shown to impact ovarian, prostate and colorectal cancers .