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

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.

http://doi.org/10.1371/journal.pone.0212850

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.

Partial Text

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 also afflicted with disease is supportive of a genetic inheritance [5].

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 [3]. Recent work has shown that many of these non-coding SNPs are found within regions of accessible chromatin, demarcated by elevated levels of H3K27ac [13]. 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 [38]. 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 [39].

 

Source:

http://doi.org/10.1371/journal.pone.0212850

 

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