Epigenetic regulation of mucin gene expression.

摘要

Gel forming mucins, such as MUC5AC, are important components of the secretory mucus that is essential in the protection and maintenance of homeostasis of airway lumen. Mucin overproduction and persistent accumulation in airways are major clinical hallmarks associated with various lung diseases and smoking related diseases. In this study, I identified a MUC5AC CpG island, located 4.7 kb upstream of the transcriptional start site that is potentially involved in the epigenetic regulation of cell type-specific, mucous cell differentiation-specific and smoke-associated MUC5AC expression. I analyzed its methylation profiles with respect to differential MUC5AC expression in primary normal human bronchial epithelial (NBE) cells, an immortalized normal bronchial epithelial cell line, HBE1 and two lung carcinoma cell lines, A549 and NCI292. My results indicate an inversely correlation between the level of MUC5AC messages and DNA methylation status in the CpG island among these cell systems. All-trans retinoic acid (RA) is required for in vitro airway mucous cell differentiation. RA at 1-100 nM stimulated MUC5AC expression and reduced DNA methylation status of the CpG island as well as the down-regulation of the levels of DNA methyl transferases, such as DNMT1, DNMT3a and DNMT3b, in these cell systems. An siRNA mediated approach identified DNMT1, but not DNMT3a and DNMT3b is potentially responsible for M UC5AC expression and DNA methylation profile.;Thus, my studies provide a fundamental understanding of the mechanism of the persistent elevation and the potential target(s) for therapeutic intervention of airway hyper-mucus production in patients with various lung diseases.