Histone Deacetylase (HDAC) 1 Controls the Expression of Beta Defensin 1 in Human Lung Epithelial Cells

Abstract

Deregulation of the expression human beta defensin 1 (DEFB1), an antimicrobial peptide, has been implicated in the pathogenesis of COPD and asthma. Since the molecular mechanisms that regulate DEFB1 gene expression are widely unknown, the epigenetic processes involved in the regulation of the constitutive expression of DEFB1 in lung epithelial cells (A549) were investigated. The data demonstrate that histone deacetylases (HDACs) participate in the regulation of DEFB1 gene expression. Inhibition of the class I HDACs, HDACs 1-3, increases DEFB1 gene expression in A549 cells. Chromatin immunoprecipitation (ChIP) assays revealed that the inhibition of the class I HDACs also results in modifications of the chromatin at the DEFB1 promoter. Histone modifications, histone H3 acetylation and H3K4 trimethylation, that are associated with transcriptional activation, were found to increase after inhibition of HDACs 1-3. Finally, RNAi knockdown experiments identified HDAC1 as the sole HDAC responsible for maintaining the constitutive level of DEFB1 transcription. Taken together, our data reveal epigenetic mechanisms which are the basis of the maintenance of the constitutive gene expression of human beta defensin 1.

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“…Polymorphisms in defensin genes are also associated with infections outside the lung (31)(32)(33). Also consistent with an important role in defense is the observation that airway insults and disease can increase defensin gene expression (34)(35)(36).…”

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“…Therefore, comprehensive gene expression analysis has recently been conducted using microarray analysis [8,9]. Moreover, epigenetic changes such as DNA methylation [6,10] and histone modification [11,12] affect the regulation of gene expression through localization around gene loci, and were shown to be important in EMT. Because histone acetylation is down-regulated in whole cells during fibrosis, histone deacetylase (HDAC) inhibitors have been used to suppress this reduction.…”