Microarray analysis of HCT116 cells with and without a 1.4kb deletion

One of the strongest associated type 2 diabetes (T2D) loci reported to date resides within the TCF7L2 gene. Previous studies point to the T allele of rs7903146 in intron 3 as the causal variant at this locus. To aid in the identification of the actual gene(s) under the influence of this variant, we first generated a CRISPR/Cas9 mediated 1.4kb deletion of the genomic region harboring rs7903146 in the HCT116 cell line followed by global gene expression analysis. HCT116 cells with or without a CRISPR/Cas9 mediated1.4kb deletion of the genomic region harboring the SNP rs7903146 were analyzed for expression, with 3 replicates per condition (DEL vs WT). We observed 99 genes with significant differential expression (FDR cut-off=10%) and an effect size of at least two-fold. We then carried out high-throughput chromosome conformation capture assays in the HCT116 and NCM460 cell lines and in colon tissue (see experiment E-MTAB-4845) in order to ascertain which of these perturbed genes’ promoters made consistent physical contact with the genomic region harboring the variant. This revealed just one gene, ACSL5, which resides in the same topologically associating domain as TCF7L2.