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Immune mediators regulate CFTR expression through a bifunctional airway-selective enhancer Zhang Z; Leir SH; Harris AMol Cell Biol 2013[Aug]; 33 (15): 2843-53An airway-selective DNase-hypersensitive site (DHS) at kb -35 (DHS-35kb) 5' to the cystic fibrosis transmembrane conductance regulator (CFTR) gene is evident in many lung cell lines and primary human tracheal epithelial cells but is absent from intestinal epithelia. The DHS-35kb contains an element with enhancer activity in 16HBE14o- airway epithelial cells and is enriched for monomethylated H3K4 histones (H3K4me1). We now define a 350-bp region within DHS-35kb which has full enhancer activity and binds interferon regulatory factor 1 (IRF1) and nuclear factor Y (NF-Y) in vitro and in vivo. Small interfering RNA (siRNA)-mediated depletion of IRF1 or overexpression of IRF2, an antagonist of IRF1, reduces CFTR expression in 16HBE14o- cells. NF-Y is critical for maintenance of H3K4me1 enrichment at DHS-35kb since depletion of NF-YA, a subunit of NF-Y, reduces H3K4me1 enrichment at this site. Moreover, depletion of SETD7, an H3K4 monomethyltransferase, reduces both H3K4me1 and NF-Y occupancy, suggesting a requirement of H3K4me1 for NF-Y binding. NF-Y depletion also represses Sin3A and reduces its occupancy across the CFTR locus, which is accompanied by an increase in p300 enrichment at multiple sites. Our results reveal that the DHS-35kb airway-selective enhancer element plays a pivotal role in regulation of CFTR expression by two independent regulatory mechanisms.|*Enhancer Elements, Genetic[MESH]|Base Sequence[MESH]|Bronchi/cytology[MESH]|CCAAT-Binding Factor/*metabolism[MESH]|Cell Line[MESH]|Cystic Fibrosis Transmembrane Conductance Regulator/*genetics[MESH]|Deoxyribonuclease I/*metabolism[MESH]|Epithelial Cells/metabolism[MESH]|Gene Expression Regulation[MESH]|Histones/metabolism[MESH]|Humans[MESH]|Interferon Regulatory Factor-1/*metabolism[MESH]|Repressor Proteins/metabolism[MESH]|Sin3 Histone Deacetylase and Corepressor Complex[MESH] |
