Regulation of airway mucin gene expression

Abstract

Mucins are important components that exert a variety of functions in cell-cell interaction, epidermal growth factor receptor signaling, and airways protection. In the conducting airways of the lungs, mucins are the major contributor to the viscoelastic property of mucous secretion, which is the major barrier to trapping inhaled microbial organism, particulates, and oxidative pollutants. The homeostasis of mucin production is an important feature in conducting airways for the maintenance of mucociliary function. Aberrant mucin secretion and accumulation in airway lumen are clinical hallmarks associated with various lung diseases, such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, emphysema, and lung cancer. Among 20 known mucin genes identified, 11 of them have been verified at either the mRNA and/or protein level in airways. The regulation of mucin genes is complicated, as are the mediators and signaling pathways. This review summarizes the current view on the mediators, the signaling pathways, and the transcriptional units that are involved in the regulation of airway mucin gene expression. In addition, we also point out essential features of epigenetic mechanisms for the regulation of these genes.

Figure 1

A rough outline of 5′ promoter regulatory regions for MUC2, MUC5AC, and MUC5B. Although this picture is not comprehensive, some specific pathways are provided to illustrate the stimulus and signal transduction pathways that activate certain transcription factors to their binding sites on the mucin promoters. The mapping of specific regulatory regions for MUC5B to their stimulus has not been elucidated in detail, but some putative sites from promoter sequence analysis are provided.

Figure 2

Theoretical mechanism of how epigenetic mechanisms can regulate mucin gene transcription. (a) Mucin gene expression is low. DNA methylation decreases the binding of transcription factors either directly or through methyl binding proteins (MBDs). DNA methyltransferases (DNMT) catalyze the transfer of methyl groups de novo to CpG sites. Nucleosome structure is relatively closed by histones deacetylated by histone deacetylases (HDAC). (b) Mucin gene expression is high. Loss of DNA methylation allows transcription factors to bind to their putative binding sites. Acetylation of histones by histone acetylases (HAT) leads to the opening of nucleosomes and increased transcription. NF-κB, nuclear factor-κB; RNA Pol II, RNA polymerase II.