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.

Single-cell sequencing of developing human gut reveals transcriptional links to childhood Crohn’s disease

“…Indeed, as shown in Figure 6E, we identified a number of such genes, many of which have been previously reported as being expressed in the fetal intestinal epithelium and linked to IBD pathogenesis. Examples include genes encoding the B lymphocyte-induced maturation protein-1 (Blimp1; encoded by the gene PRDM1) (Harper et al, 2011;Muncan et al, 2011;Ellinghaus et al, 2013), Wnt signalling transcription factor TCF4 (Barker et al, 1999;Wehkamp et al, 2007) as well as C-MYC, a transcription factor controlling the differentiation of progenitor cell types (Bettess et al, 2005;Matthews et al, 2019). Furthermore, our analyses also identified several novel transcription factors, expression of which becomes reactivated in the inflamed, regenerative CD epithelium.…”

Taking the Myc out of cancer: toward therapeutic strategies to directly inhibit c-Myc

“…c-Myc is strongly linked to renal cystic diseases and onset of polycystic kidney disease (PKD) in animal models, suggesting the potential for c-Myc inhibition in PKD treatment. In the spectrum of inflammatory illnesses, c-Myc dysfunction has been reported in patients with Crohn’s disease [ 56 ] and other chronic gastrointestinal disorders [ 57 ]. In a model of autoimmune encephalomyelitis, treatment with c-Myc inhibitor 10058-F4 suppressed the ability of Th1-differentiated T-cells to induce inflammation [ 58 ].…”

LncRNA MALAT1 potentiates inflammation disorder in Parkinson's disease

“…up-regulation of MYC in Crohn's disease) could be modulated by certain SNPs (e.g. rs6651252) (Matthews et al, 2019).…”