The non-coding variant rs1800734 enhances DCLK3 expression through long-range interaction and promotes colorectal cancer progression.
- Liu NQ Faculty of Science, Department of Molecular Biology, Radboud University, RIMLS, PO BOX 9101, 6500HB Nijmegen, The Netherlands.
- Ter Huurne M Faculty of Science, Department of Molecular Biology, Radboud University, RIMLS, PO BOX 9101, 6500HB Nijmegen, The Netherlands.
- Nguyen LN Faculty of Science, Department of Molecular Biology, Radboud University, RIMLS, PO BOX 9101, 6500HB Nijmegen, The Netherlands.
- Peng T Faculty of Science, Department of Molecular Biology, Radboud University, RIMLS, PO BOX 9101, 6500HB Nijmegen, The Netherlands.
- Wang SY Faculty of Science, Department of Molecular Biology, Radboud University, RIMLS, PO BOX 9101, 6500HB Nijmegen, The Netherlands.
- Studd JB Division of Genetics and Epidemiology, Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG Surrey, UK.
- Joshi O Faculty of Science, Department of Molecular Biology, Radboud University, RIMLS, PO BOX 9101, 6500HB Nijmegen, The Netherlands.
- Ongen H Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 1211, Switzerland.
- Bramsen JB Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark.
- Yan J Division of Functional Genomics and Systems Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE 141 83 Stockholm, Sweden.
- Andersen CL Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark.
- Taipale J Division of Functional Genomics and Systems Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE 141 83 Stockholm, Sweden.
- Dermitzakis ET Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 1211, Switzerland.
- Houlston RS Division of Genetics and Epidemiology, Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG Surrey, UK.
- Hubner NC Faculty of Science, Department of Molecular Biology, Radboud University, RIMLS, PO BOX 9101, 6500HB Nijmegen, The Netherlands.
- Stunnenberg HG Faculty of Science, Department of Molecular Biology, Radboud University, RIMLS, PO BOX 9101, 6500HB Nijmegen, The Netherlands.
- 2017-02-15
Published in:
- Nature communications. - 2017
Alleles
CRISPR-Cas Systems
Cell Line, Tumor
Colonic Neoplasms
Colorectal Neoplasms
DNA Methylation
DNA-Binding Proteins
Disease Progression
Epigenesis, Genetic
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Intracellular Signaling Peptides and Proteins
MutL Protein Homolog 1
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
Protein-Serine-Threonine Kinases
Proteome
Proteomics
Transcription Factors
English
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.
- Language
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- English
- Open access status
- gold
- Identifiers
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- DOI 10.1038/ncomms14418
- PMID 28195176
- Persistent URL
- https://sonar.ch/global/documents/232692
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