Functional characterization of the 12p12.1 renal cancer-susceptibility locus implicates BHLHE41
| Autor: | David Roberson, Lea Jessop, Timothy A. Myers, Mitchell J. Machiela, Sarah Wagner, Daniel Henrion, Leandro M. Colli, Pierre Bigot, Caroline Eymerit, Julie Carrouget, Stephen J. Chanock |
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| Přispěvatelé: | Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Science [SDV]Life Sciences [q-bio] General Physics and Astronomy Locus (genetics) Single-nucleotide polymorphism [SDV.CAN]Life Sciences [q-bio]/Cancer Biology urologic and male genital diseases Polymorphism Single Nucleotide General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Mice Atlases as Topic Cell Line Tumor Basic Helix-Loop-Helix Transcription Factors SNP Animals Humans Luciferase Genetic Predisposition to Disease Allele Enhancer Transcription factor Carcinoma Renal Cell Alleles Genetic association Multidisciplinary Chromosomes Human Pair 12 Base Sequence Computational Biology General Chemistry Interleukin-11 Molecular biology Kidney Neoplasms Transcription Factor AP-1 030104 developmental biology Genetic Loci Neoplasm Transplantation Protein Binding |
| Zdroj: | Nature Communications Nature Communications, Nature Publishing Group, 2016, 7 (12098), pp.1-10. ⟨10.1038/ncomms12098⟩ Nature Communications, Vol 7, Iss 1, Pp 1-10 (2016) |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/ncomms12098⟩ |
| Popis: | Genome-wide association studies have identified multiple renal cell carcinoma (RCC) susceptibility loci. Here, we use regional imputation and bioinformatics analysis of the 12p12.1 locus to identify the single-nucleotide polymorphism (SNP) rs7132434 as a potential functional variant. Luciferase assays demonstrate allele-specific regulatory activity and, together with data from electromobility shift assays, suggest allele-specific differences at rs7132434 for AP-1 transcription factor binding. In an analysis of The Cancer Genome Atlas data, SNPs highly correlated with rs7132434 show allele-specific differences in BHLHE41 expression (trend P value=6.3 × 10−7). Cells overexpressing BHLHE41 produce larger mouse xenograft tumours, while RNA-seq analysis reveals that constitutively increased BHLHE41 induces expression of IL-11. We conclude that the RCC risk allele at 12p12.1 maps to rs7132434, a functional variant in an enhancer that upregulates BHLHE41 expression which, in turn, induces IL-11, a member of the IL-6 cytokine family. A common susceptibility haplotype for renal cell carcinoma is located on chromosome 12p12.1. Here, the authors show that the variant rs7132434 alters binding of the AP-1 transcription factor, which increases the expression of BHLHE41 in renal cells. |
| Databáze: | OpenAIRE |
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