The non-coding variant rs1800734 enhances DCLK3 expression through long-range interaction and promotes colorectal cancer progression.
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ICR Authors
Authors
Liu, NQ
Ter Huurne, M
Nguyen, LN
Peng, T
Wang, S-Y
Studd, JB
Joshi, O
Ongen, H
Bramsen, JB
Yan, J
Andersen, CL
Taipale, J
Dermitzakis, ET
Houlston, RS
Hubner, NC
Stunnenberg, HG
Ter Huurne, M
Nguyen, LN
Peng, T
Wang, S-Y
Studd, JB
Joshi, O
Ongen, H
Bramsen, JB
Yan, J
Andersen, CL
Taipale, J
Dermitzakis, ET
Houlston, RS
Hubner, NC
Stunnenberg, HG
Document Type
Journal Article
Date
2017-02-14
Date Accepted
2016-12-28
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.
Citation
Nature communications, 2017, 8 pp. 14418 - ?
Source Title
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
Collections
Research Team
Cancer Genomics