Abstract
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.
Highlights
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 [1]
The list of variants associated with IBD has grown to include over 200 distinct loci [2,6,7,8]. While these results clearly demonstrate the power of Genome-wide association studies (GWAS) to inform on disease pathogenesis, approximately 80–90% of the identified alleles map to non-coding regions of the genome, many of which are in gene-poor regions [6]
By overlapping β-catenin Chromatin Immunoprecipitation (ChIP)-Seq peak regions with positions of IBD single nucleotide polymorphisms (SNPs), we identified the CD-associated SNP, rs6651252, as a leading candidate (Fig 1A)
Summary
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 [1]. 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 afflicted with disease is supportive of a genetic inheritance [5].
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