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Epigenetic Regulation of Airway MUC gene expression by smoke

Institution: University of California, Davis
Investigator(s): Reen Wu, Ph.D.
Award Cycle: 2007 (Cycle 16) Grant #: 16RT-0127 Award: $419,528
Subject Area: Pulmonary Disease
Award Type: Research Project Awards

Initial Award Abstract
Cigarette smoke is well known to cause human diseases, such as chronic bronchitis, emphysema, chronic obstructive pulmonary disease (COPD) and lung cancers. One of the clinical hall marks associated with these diseases is elevated mucin production and accumulation in airways. The nature of the cause of smoke on these diseases and mucin over-production is incompletely understood.

Although current smokes are at high risk for these diseases, not all smokers develop these diseases. In addition, ex-smokers, even after decades-long smoking cessation, are still in high risk for the development of these diseases. Recent data from various laboratories and data from our preliminary studies have shown a persistent increase/decrease of the expression of various genes, including a persistent increase of MUC5AC, associated with the smoking history. Based on these findings, we propose that epigenetic regulations represent another mechanism for this phenomenon. Thus, the central hypothesis proposed in this study is that cigarette smoke (CS) is a potent epigenetic agent that has a profound effect on airway epithelial cell gene expression.

To test this hypothesis, two main Specific aims are proposed. Specific aim 1 is to test the hypothesis that CS regulates airway MUC5AC expression through an epigenetic mechanism. Specifically, we will characterize the changes in the chromatin context of MUC5AC in CS-exposed primary human airway epithelial cells and to elucidate the molecular and cellular basis associated with these changes by siRNA and inhibitor approaches. Specific aim 2 is to elucidate the molecular basis of the epigenetic mechanism of CS-induced/suppressed airway gene expression in primary human airway epithelial cell cultures. Specifically, we will use chromatin immunoprecipitation (ChIP) approach to carry out ChIP-chip assay and microarray analysis to elucidate genome-wide changes in primary human airway epithelial cells exposed to CS. We will then use various siRNA and inhibitor approaches to elucidate the molecular and cellular basis associated with these changes. Several persistently induced/suppressed genes by CS have been identified. These are: PLA2G10, S100A10, TM4SF1, CTTN, GMDS, HN1, IMPA2, AKR1B10, CEACAM5, CEACAM6, KRT15, MT1F, MT1X, CYP2A6, EGFL9, EPAS1, and HSPA2, in addition to MUC5AC. The elucidation of epigenetic changes at the genome-wide level as well as on MUC5AC will provide the fundamental test of the proposed hypothesis.

Requirements for two proximal NF-kappa B binding sites and Ikappa B-zeta in IL-17A-induced human beta-defensin 2 expression by conducting airway Epithelium.
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Kao CY, Kim C., Huang F, Wu R. ART
Yr: 2008 Vol: 283 (22) Nbr: Abs: Pg: 15309-18

Potentiation of IL-19 expression in airway epithelia by IL-17A and IL-4/IL-13: important implications in asthma.
Periodical: Journal of Allergy and Clinical Immunology Index Medicus:
Authors: Huang F, Wachi S, Thai P, Loukoianov A, Tan KH, Forteza RM, Wu R ART
Yr: 2008 Vol: 121 (6) Nbr: Abs: Pg: 1415-21