The Crohn's disease associated SNP rs6651252 impacts MYC gene expression in human colonic epithelial cells

• Published in: PloS one 2019-02, Vol.14 (2), p.e0212850-e0212850
• Main Authors: Matthews, Stephen M, Eshelman, Melanie A, Berg, Arthur S, Koltun, Walter A, Yochum, Gregory S
• Format: Article
• Language: English
• Subjects: Alleles; Aprotinin; Biochemistry; Biology and Life Sciences; c-Myc protein; Cell cycle; Chromosome 8; Chromosomes; Chromosomes, Human, Pair 8 - genetics; Chromosomes, Human, Pair 8 - metabolism; Colon - metabolism; Colon - pathology; Colorectal cancer; CRISPR; Crohn Disease - genetics; Crohn Disease - metabolism; Crohn Disease - pathology; Crohn's disease; Deoxyribonucleic acid; Deserts; DNA; EDTA; Enhancer Elements, Genetic; Epigenetic inheritance; Epithelial cells; Epithelial Cells - metabolism; Epithelial Cells - pathology; Gastroenterology; Gastrointestinal diseases; Gastrointestinal system; Gastrointestinal tract; Gene expression; Gene Expression Regulation; Gene mapping; Genes; Genetic aspects; Genetic modification; Genetic polymorphisms; Genome editing; Genome-wide association studies; Genomes; Genomics; HCT116 Cells; HEK293 Cells; Humans; Inflammation; Inflammatory bowel disease; Inflammatory bowel diseases; Intestine; Medicine; Medicine and Health Sciences; Molecular biology; Myc protein; Pathogenesis; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins c-myc - biosynthesis; Proto-Oncogene Proteins c-myc - genetics; Research and analysis methods; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Surgery; Transcription (Genetics); Transcription factors; Wnt protein; Wnt Signaling Pathway - genetics
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0212850

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.