title: The non-coding variant rs1800734 enhances DCLK3 expression through long-range interaction and promotes colorectal cancer progression.
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.
authors.affiliation: Faculty of Science, Department of Molecular Biology, Radboud University, RIMLS, PO BOX 9101, 6500HB Nijmegen, The Netherlands.
authors.forename: Ning Qing
authors.initials: NQ
authors.lastname: Liu
authors.affiliation: Faculty of Science, Department of Molecular Biology, Radboud University, RIMLS, PO BOX 9101, 6500HB Nijmegen, The Netherlands.
authors.forename: Menno
authors.initials: M
authors.lastname: Ter Huurne
authors.affiliation: Faculty of Science, Department of Molecular Biology, Radboud University, RIMLS, PO BOX 9101, 6500HB Nijmegen, The Netherlands.
authors.forename: Luan N
authors.initials: LN
authors.lastname: Nguyen
authors.affiliation: Faculty of Science, Department of Molecular Biology, Radboud University, RIMLS, PO BOX 9101, 6500HB Nijmegen, The Netherlands.
authors.forename: Tianran
authors.initials: T
authors.lastname: Peng
authors.affiliation: Faculty of Science, Department of Molecular Biology, Radboud University, RIMLS, PO BOX 9101, 6500HB Nijmegen, The Netherlands.
authors.forename: Shuang-Yin
authors.initials: SY
authors.lastname: Wang
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG Surrey, UK.
authors.forename: James B
authors.identifier: 0000-0002-7157-754X
authors.initials: JB
authors.lastname: Studd
authors.affiliation: Faculty of Science, Department of Molecular Biology, Radboud University, RIMLS, PO BOX 9101, 6500HB Nijmegen, The Netherlands.
authors.forename: Onkar
authors.initials: O
authors.lastname: Joshi
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 1211, Switzerland.
authors.forename: Halit
authors.initials: H
authors.lastname: Ongen
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark.
authors.forename: Jesper B
authors.initials: JB
authors.lastname: Bramsen
authors.affiliation: Division of Functional Genomics and Systems Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE 141 83 Stockholm, Sweden.|Ludwig Institute for Cancer Research, 9500 Gilman Drive, La Jolla, California 92093, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark.
authors.forename: Claus L
authors.initials: CL
authors.lastname: Andersen
authors.affiliation: Division of Functional Genomics and Systems Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE 141 83 Stockholm, Sweden.
authors.forename: Jussi
authors.initials: J
authors.lastname: Taipale
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 1211, Switzerland.
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG Surrey, UK.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.affiliation: Faculty of Science, Department of Molecular Biology, Radboud University, RIMLS, PO BOX 9101, 6500HB Nijmegen, The Netherlands.
authors.forename: Nina C
authors.initials: NC
authors.lastname: Hubner
authors.affiliation: Faculty of Science, Department of Molecular Biology, Radboud University, RIMLS, PO BOX 9101, 6500HB Nijmegen, The Netherlands.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
mesh_terms: D000483:Alleles; D064113:CRISPR-Cas Systems; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins; D018450:Disease Progression; D000089742:Doublecortin-Like Kinases; D044127:Epigenesis, Genetic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D000070957:MutL Protein Homolog 1 / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D020543:Proteome; D040901:Proteomics; D014157:Transcription Factors
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C501486:MLH1 protein, human; D020543:Proteome; D014157:Transcription Factors; C117347:DCLK1 protein, human; D000089742:Doublecortin-Like Kinases; D017346:Protein Serine-Threonine Kinases; D000070957:MutL Protein Homolog 1