Regulatory dynamics of 11p13 suggest a role for EHF in modifying CF lung disease severity
| Autor: | Kay-Marie Lamar, Rui Yang, Ann Harris, Andrew D. Hoffmann, Sujana Ghosh, Shih Hsing Leir, Sara L. Fossum, Matthew Xu, Jenny L. Kerschner, Sarah Wachtel, Lindsay R. Stolzenburg |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cystic Fibrosis medicine.disease_cause Polymorphism Single Nucleotide Severity of Illness Index 03 medical and health sciences Genetics medicine Humans Genetic Predisposition to Disease Enhancer Transcription factor Cells Cultured Mutation biology Chromosomes Human Pair 11 ETS transcription factor family Gene regulation Chromatin and Epigenetics ETS Homologous Factor Promoter Molecular biology Chromatin Cystic fibrosis transmembrane conductance regulator Enhancer Elements Genetic 030104 developmental biology Gene Expression Regulation Genetic Loci CTCF biology.protein Caco-2 Cells K562 Cells Genome-Wide Association Study Transcription Factors |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| DOI: | 10.1093/nar/gkx482 |
| Popis: | Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), but are not good predictors of lung phenotype. Genome-wide association studies (GWAS) previously identified additional genomic sites associated with CF lung disease severity. One of these, at chromosome 11p13, is an intergenic region between Ets homologous factor (EHF) and Apaf-1 interacting protein (APIP). Our goal was to determine the functional significance of this region, which being intergenic is probably regulatory. To identify cis-acting elements, we used DNase-seq and H3K4me1 and H3K27Ac ChIP-seq to map open and active chromatin respectively, in lung epithelial cells. Two elements showed strong enhancer activity for the promoters of EHF and the 5′ adjacent gene E47 like ETS transcription factor 5 (ELF5) in reporter gene assays. No enhancers of the APIP promoter were found. Circular chromosome conformation capture (4C-seq) identified direct physical interactions of elements within 11p13. This confirmed the enhancer-promoter associations, identified additional interacting elements and defined topologically associating domain (TAD) boundaries, enriched for CCCTC-binding factor (CTCF). No strong interactions were observed with the APIP promoter, which lies outside the main TAD encompassing the GWAS signal. These results focus attention on the role of EHF in modifying CF lung disease severity. |
| Databáze: | OpenAIRE |
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