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

TY - JOUR

T1 - The non-coding variant rs1800734 enhances DCLK3 expression through long-range interaction and promotes colorectal cancer progression

AU - Liu, Ning Qing

AU - Ter Huurne, Menno

AU - Nguyen, Luan N

AU - Peng, Tianran

AU - Wang, Shuang-Yin

AU - Studd, James B

AU - Joshi, Onkar

AU - Ongen, Halit

AU - Bramsen, Jesper B

AU - Yan, Jian

AU - Andersen, Claus L

AU - Taipale, Jussi

AU - Dermitzakis, Emmanouil T

AU - Houlston, Richard S

AU - Hubner, Nina C

AU - Stunnenberg, Hendrik G

PY - 2017/2/14

Y1 - 2017/2/14

N2 - 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.

AB - 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.

KW - Journal Article

UR - http://www.scopus.com/inward/record.url?scp=85012916015&partnerID=8YFLogxK

U2 - 10.1038/ncomms14418

DO - 10.1038/ncomms14418

M3 - Journal article

C2 - 28195176

SN - 2041-1723

VL - 8

SP - 14418

JO - Nature Communications

JF - Nature Communications

M1 - 14418

ER -