The non-coding variant rs1800734 enhances DCLK3 expression through long-range interaction and promotes colorectal cancer progression

Ning Qing Liu,Onkar Joshi,Jussi Taipale,James B Studd,Tianran Peng,Emmanouil T Dermitzakis,Luan N Nguyen,Menno Ter Huurne,Jian Yan,Shuang-Yin Wang,Richard S Houlston,Nina C Hubner,Claus L Andersen,Hendrik G Stunnenberg,Halit Ongen,Jesper B Bramsen

doi:10.1038/ncomms14418

Abstract

Genome-wide association studies have identified a great number of non-coding risk variants for colorectal cancer (CRC). To date, the majority of these variants have not been functionally studied. Identification of allele-specific transcription factor (TF) binding is of great importance to understand regulatory consequences of such variants. A recently developed proteome-wide analysis of disease-associated SNPs (PWAS) enables identification of TF-DNA interactions in an unbiased manner. Here we perform a large-scale PWAS study to comprehensively characterize TF-binding landscape that is associated with CRC, which identifies 731 allele-specific TF binding at 116 CRC risk loci. This screen identifies the A-allele of rs1800734 within the promoter region of MLH1 as perturbing the binding of TFAP4 and consequently increasing DCLK3 expression through a long-range interaction, which promotes cancer malignancy through enhancing expression of the genes related to epithelial-to-mesenchymal transition.

Highlights

Genome-wide association studies have identified a great number of non-coding risk variants for colorectal cancer (CRC)
As the outcome from our proteome-wide analysis of disease-associated Single-nucleotide polymorphisms (SNPs) (PWAS) screen, we further investigated the functions of a SNP located in the promoter region of MLH1 gene (MLH1-93G4A or rs1800734), which has been associated with the risk of several cancer types including CRC9,21,22, endometrial cancer[23], glioblastoma[24] and lung cancer[25]
transcription factor (TF)– DNA interactome data showed a clear enrichment for TFs (Supplementary Fig. 1a) and the altered binding events mediated by known TFs (Supplementary Data 3) showed stronger allele preference than other interactions (P 1⁄4 4.4 Â 10 À 6, Mann– Whitney U-test) (Supplementary Fig. 1b)

Summary

Introduction

Genome-wide association studies have identified a great number of non-coding risk variants for colorectal cancer (CRC). We perform a large-scale PWAS study to comprehensively characterize TF-binding landscape that is associated with CRC, which identifies 731 allele-specific TF binding at 116 CRC risk loci. This screen identifies the A-allele of rs1800734 within the promoter region of MLH1 as perturbing the binding of TFAP4 and increasing DCLK3 expression through a long-range interaction, which promotes cancer malignancy through enhancing expression of the genes related to epithelial-to-mesenchymal transition. We identified a molecular function of this SNP in promoting cancer malignancy through a novel gene target named DCLK3

Methods

Results

Conclusion