Abstract
Cigarette smoke (CS) is one of the major risk factors for many pulmonary diseases, including chronic obstructive pulmonary disease (COPD) and lung cancer. The first line of defense for CS exposure is the bronchial epithelial cells. Elucidation of the epigenetic changes during CS exposure is key to gaining a mechanistic understanding into how mature and differentiated bronchial epithelial cells respond to CS. Therefore, we performed epigenomic profiling in conjunction with transcriptional profiling in well-differentiated human bronchial epithelial (HBE) cells cultured in air-liquid interface (ALI) exposed to the vapor phase of CS. The genome-wide enrichment of histone 3 lysine 27 acetylation was detected by chromatin immunoprecipitation followed by next generation sequencing (ChIP-Seq) in HBE cells and suggested the plausible binding of specific transcription factors related to CS exposure. Additionally, interrogation of ChIP-Seq data with gene expression profiling of HBE cells after CS exposure for different durations (3 hours, 2 days, 4 days) suggested that earlier epigenetic changes (3 hours after CS exposure) may be associated with later gene expression changes induced by CS exposure (4 days). The integration of epigenetics and gene expression data revealed signaling pathways related to CS-induced epigenetic changes in HBE cells that may identify novel regulatory pathways related to CS-induced COPD.
Highlights
Among the vast number of environmental exposures, cigarette smoke (CS) exposure remains one of the greatest avoidable environmental health risks
To characterize Cigarette smoke (CS)-induced chromatin changes at a genome-wide scale in human bronchial epithelium and infer plausible mechanisms, human bronchial epithelial (HBE) cells were cultured at air-liquid interface (ALI) and exposed to the vapor phase of CS to model in vivo effects of CS in human bronchial epithelium
After 21 days of post-ALI culture, cells expressed significantly increased levels of FOXJ1, RFX3 and MUC5AC, suggesting efficient differentiation of HBE cells at ALI (Fig. 1A). This in vitro model recapitulated the morphology of human bronchial epithelium as indicated by the organization of ciliated cells stained for beta IV -tubulin and goblet cells stained for MUC5AC into pseudo-stratified, well-differentiated epithelium[9] (Fig. 1B)
Summary
Among the vast number of environmental exposures, cigarette smoke (CS) exposure remains one of the greatest avoidable environmental health risks. Two major gaps remain: (1) lack of direct evidence for histone modification at a genome-wide scale after CS exposure; (2) absence of data in human bronchial epithelium exposed to the vapor phase of cigarette smoke. We hypothesized that CS-induced genome-wide changes of histone modifications may contribute to CS-induced gene expression changes in human airway epithelium that are pathological to CS-related respiratory diseases. To characterize CS-induced chromatin changes at a genome-wide scale in human bronchial epithelium and infer plausible mechanisms, HBE cells were cultured at air-liquid interface (ALI) and exposed to the vapor phase of CS to model in vivo effects of CS in human bronchial epithelium. We performed a systematic and unbiased global mapping of CS-induced H3K27Ac changes and assessed correlation of chromatin modification changes with sub-chronic CS-induced gene expression changes (day 1 to day 4) in human bronchial epithelial cells cultured at ALI
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