Immune Mediators Regulate CFTR Expression through a Bifunctional Airway-Selective Enhancer

Zhaolin Zhang, Shih Hsing Leir, Ann Harris*

*Corresponding author for this work

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

An 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.

Original languageEnglish (US)
Pages (from-to)2843-2853
Number of pages11
JournalMolecular and cellular biology
Volume33
Issue number15
DOIs
StatePublished - Aug 1 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Immune Mediators Regulate CFTR Expression through a Bifunctional Airway-Selective Enhancer'. Together they form a unique fingerprint.

  • Cite this