Epigenetic regulation of proinflammatory chemokines in Cystic Fibrosis lung epithelium
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE(2017)
Abstract
Abstract Functional loss of CFTR in lung epithelial cells leads to pulmonary disease in Cystic Fibrosis (CF) patients. Our preliminary data indicates that proinflammatory chemokines and cytokines are spontaneously released by Human Bronchial Epithelial (HBE) cells established from CF patients and the spontaneous release can be abolished by a bromodomain inhibitor, a small molecule that inhibits epigenetic enhancement of gene transcription. Epigenetics alter gene expression in many other diseases, thus, this mechanism could also be responsible for the dysregulation of inflammatory mediators observed in the CF airway. We hypothesize that the enhanced production of proinflammatory mediators observed in CF airways are in part controlled by an epigenetic regulatory program. RNA-seq analysis revealed a dramatic upregulation of chemokine genes in the airway epithelium from CF patients, which correlated with downregulation of histone deacetylases, suggesting chemokine expression in CF airway can be modified by histone acetylation. In vitro, chemokine productions in polarized HBE cells from CF donors are also enhanced and are sensitive to BET inhibition. ATAC-seq analysis on HBE cells derived from control and CF donors was conducted and more peaks were observed in CF cells at the promoter regions of several chemokine genes suggesting these loci are more accessible compared to control HBE cells. These data strongly implicate that pro-inflammatory environment in CF lungs epigenetically enhances chemokines production through repressing histone deacetylases, suggesting that therapeutic approaches aiming to reverse the consequence of losing histone deacetylases can be beneficial to CF patients through reducing lung inflammation.
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Key words
proinflammatory chemokines,cystic fibrosis,epigenetic regulation
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