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

Author

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  • Ning Qing Liu

    (Faculty of Science, Radboud University
    Present address: Division of Gene Regulation (B4), The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands)

  • Menno ter Huurne

    (Faculty of Science, Radboud University)

  • Luan N. Nguyen

    (Faculty of Science, Radboud University)

  • Tianran Peng

    (Faculty of Science, Radboud University)

  • Shuang-Yin Wang

    (Faculty of Science, Radboud University)

  • James B. Studd

    (Institute of Cancer Research)

  • Onkar Joshi

    (Faculty of Science, Radboud University)

  • Halit Ongen

    (University of Geneva Medical School)

  • Jesper B Bramsen

    (Aarhus University Hospital)

  • Jian Yan

    (Karolinska Institutet
    Ludwig Institute for Cancer Research)

  • Claus L. Andersen

    (Aarhus University Hospital)

  • Jussi Taipale

    (Karolinska Institutet)

  • Emmanouil T. Dermitzakis

    (University of Geneva Medical School)

  • Richard S. Houlston

    (Institute of Cancer Research)

  • Nina C. Hubner

    (Faculty of Science, Radboud University)

  • Hendrik G. Stunnenberg

    (Faculty of Science, Radboud University)

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.

Suggested Citation

  • 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 & Emma, 2017. "The non-coding variant rs1800734 enhances DCLK3 expression through long-range interaction and promotes colorectal cancer progression," Nature Communications, Nature, vol. 8(1), pages 1-10, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14418
    DOI: 10.1038/ncomms14418
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