Mining open chromatin to determine the molecular basis of the CF lung disease modifier region at chr11p13.
Though CF is caused by mutations in the CFTR gene, CFTR genotype is not a good predictor of disease severity, implicating other “genetic modifiers”. We are investigating the molecular basis of genetic elements affecting lung disease severity in CF. A genome-wide association study (GWAS) coordinated by our collaborators Drs. Knowles and O’Neal at the University of North Carolina at Chapel Hill, demonstrated that SNPs at chr11p13 tracked with this phenotype. These SNPs lie in an intergenic region that is flanked on one side by two epithelial-selective TFs, Ets homologous factor (EHF) and E47-like 5 (ELF5), and on the other sided by a gene involved in apoptosis Apaf-1 interacting protein (APIP). We are using both gene-centric and regulatory element-centric approaches to determine how this region of chromosome 11 impacts CF lung disease severity. We showed that the EHF transcription factor network has a key role in lung epithelial function and is a strong candidate as a CF modifier gene.
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Current Projects:
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Using CRISPR/Cas9 protocols to manipulate enhancers across chr11p13 and determine their impact on gene expression and regional chromatin architecture.
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To determine regulatory mechanisms for ELF5 and EHF, their functional reciprocity, and their transcriptional networks in primary airway epithelial cells.
Recent Publications:
Fossum, S.L., Mutolo, M.J., Tugores, A., Ghosh, S., Randell, SH., Jones, L.C., Leir, S-H., Harris, A. (2017) Ets Homologous Factor (EHF) has critical roles in epithelial dysfunction in airway disease. J. Biol. Chem. 292:10938-10949. Epub 2017 May 1.
Stolzenburg, L.R., Yang, R., Kerschner, J.L., Fossum S.L., Xu, M., Hoffman, A., Ghosh, S., Lamar, K-M., Wachtel, S., Leir, S-H., Harris, A. (2017) Regulatory dynamics of 11p13 suggest a role for EHF in modifying CF lung disease severity. Nucleic Acids Research. 45:8773-8784 Epub 2017 May 26.
Stolzenburg, L.R., and Harris, A. (2018) Microvesicle-mediated delivery of miR-1343: impact on markers of fibrosis. Cell and Tissue Research. 371(2):325-338. EPub. Oct 11