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

PloS One
Stephen M MatthewsGregory S Yochum

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.

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Citations

Apr 3, 2021·American Journal of Human Genetics·Minal CaliskanJoseph C Maranville
Jul 23, 2021·International Journal of Immunogenetics·Huimin Yang
Dec 11, 2021·Journal of Gastroenterology and Hepatology·Laurence Don Wai LuuNatalia Castaño-Rodríguez

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Methods Mentioned

BETA
PCR
Immunoprecipitation
transfection
pull-down
ChIP-Seq
ChIP
genotyping

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