Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 23, Issue 11, Pages 7726-7740Publisher
WILEY
DOI: 10.1111/jcmm.14646
Keywords
airway epithelial biology; chromatin architecture; cis-regulatory elements; E74-like factor 5; enhancers; ETS family transcription factors; ETS-homologous factor; lung diseases; lung epithelium; regulation of gene expression
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Funding
- Cystic Fibrosis Foundation [Harris 15/17XX0, Ebron 18F0, Harris 16G0, Harris 18P0]
- National Institutes of Health [HL146010, R01 HL117843, T32 GM008056]
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E74-like factor 5 (ELF5) and ETS-homologous factor (EHF) are epithelial selective ETS family transcription factors (TFs) encoded by genes at chr11p13, a region associated with cystic fibrosis (CF) lung disease severity. EHF controls many key processes in lung epithelial function so its regulatory mechanisms are important. Using CRISPR/Cas9 technology, we removed three key cis-regulatory elements (CREs) from the chr11p13 region and also activated multiple open chromatin sites with CRISPRa in airway epithelial cells. Deletion of the CREs caused subtle changes in chromatin architecture and site-specific increases in EHF and ELF5. CRISPRa had most effect on ELF5 transcription. ELF5 levels are low in airway cells but higher in LNCaP (prostate) and T47D (breast) cancer cells. ATAC-seq in these lines revealed novel peaks of open chromatin at the 5' end of chr11p13 associated with an expressed ELF5 gene. Furthermore, 4C-seq assays identified direct interactions between the active ELF5 promoter and sites within the EHF locus, suggesting co-ordinate regulation between these TFs. ChIP-seq for ELF5 in T47D cells revealed ELF5 occupancy within EHF introns 1 and 6, and siRNA-mediated depletion of ELF5 enhanced EHF expression. These results define a new role for ELF5 in lung epithelial biology.
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