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

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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

37 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Artikelnummer14418
TijdschriftNature Communications
Volume8
DOI's
StatusGepubliceerd - 14 feb. 2017
Extern gepubliceerdJa

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