Histone demethylation and acetylation are involved in the epigenetic regulation of epithelial-mesenchymal transition (EMT)

Epithelial-Mesenchymal transition is an important process in the repair and maintenance of the epithelial barrier in the lungs. During EMT epithelial cells gain increased motility and increased production of proteins, such as collagen and actin. EMT is important in a number of lung diseases, and is associated with fibrosis in asthma, remodeling in COPD and increased metastasis and invasiveness in lung cancer. Epigenetic regulation including post-translational modifications of histones is thought to play an important role in gene regulation and cell differentiation. Histone modifications such as acetylation and methylation are recognized by transcriptional co-factors such as Brd4 and JMJD3. We used type 1, alpha 1, collagen, encoded by the gene COL1A1 , as a marker of the EMT process normal human bronchial epithelial cells. Stimulation with TGFβ1 strongly induced COL1A1 transcription. Pretreating epithelial cells with the H3K27 demethylase JMJD3 inhibitors (GSKJ1 and GSKJ4) and the Brd4 inhibitor (JQ1) significantly inhibited TGFβ1 induced collagen expression. Our results indicate that following stimulation of epithelial cells with TGFβ1 the histones in the COL1A1 promoter region are demethylated by JMJD3 allowing transcriptional activation. As Brd4 recognizes changes to histone acetylation our results indicate that during EMT the histones of the COL1A1 promoter become acetylated. Therefore epigenetic modification of histones plays a key role during the process of TGFβ1 induced EMT.