GSE131084
Coordinate regulation of ELF5 and EHF at the chr11p13 modifier region
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 cis-regulatory elements (CREs) from the chr11p13 region in airway epithelial cells. Deletion of two enhancers and one CRE within a stretch enhancer at the EHF locus caused subtle changes in chromatin architecture, and though EHF expression did not change, ELF5 abundance increased. ELF5 is normally very low in airway cells so we next examined cell types that express more ELF5 (LNCaP and T47D). ATAC-seq experiments in these lines revealed novel peaks of open chromatin (potential CREs) at the 5' end of chr11p13 that were 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 coordinate 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 repressed EHF expression. These results define a new role for ELF5 in lung epithelial biology. Overall design: IDR OMNI-ATAC-seq profiles of open chromatin were generated from 2 independent replicates of libraries for 3 cell lines: Calu3, LNCaP, and T47D