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

Stephen M. Matthews, Melanie A. Eshelman, Arthur Berg, Walter Koltun, Gregory Yochum

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere0212850
JournalPloS one
Volume14
Issue number2
DOIs
StatePublished - Feb 1 2019

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Crohn disease
Polymorphism
Gene expression
Crohn Disease
single nucleotide polymorphism
Single Nucleotide Polymorphism
epithelial cells
Nucleotides
Epithelial Cells
Alleles
alleles
Gene Expression
gene expression
inflammatory bowel disease
Inflammatory Bowel Diseases
Genes
Transcription Factor 7-Like 2 Protein
genes
Clustered Regularly Interspaced Short Palindromic Repeats
proto-oncogenes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

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title = "The Crohn’s disease associated SNP rs6651252 impacts MYC gene expression in human colonic epithelial cells",
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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The Crohn’s disease associated SNP rs6651252 impacts MYC gene expression in human colonic epithelial cells. / Matthews, Stephen M.; Eshelman, Melanie A.; Berg, Arthur; Koltun, Walter; Yochum, Gregory.

In: PloS one, Vol. 14, No. 2, e0212850, 01.02.2019.

Research output: Contribution to journalArticle

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