The Non-coding Variant Rs1800734 Enhances DCLK3 Expression Through Long-range Interaction and Promotes Colorectal Cancer Progression

Overview

Journal Nat Commun

Specialty Biology

Date 2017 Feb 15

PMID 28195176

Citations 36

Authors

Ning Qing Liu

Menno Ter Huurne

Luan N Nguyen

Tianran Peng

Shuang-Yin Wang

James B Studd

Onkar Joshi

Halit Ongen

Jesper B Bramsen

Jian Yan

Claus L Andersen

Jussi Taipale

Emmanouil T Dermitzakis

Richard S Houlston

Nina C Hubner

Hendrik G Stunnenberg

Affiliations

Soon will be listed here.

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.

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