Friday, November 22, 2024
11/22/2024
PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF) is a fatal lung disorder of unknown etiology. IPF is characterized by altered epigenetic state. Epigenetic alterations are potentially reversible, thus are attractive therapeutic targets. Chromatin structural remodeling through histone post- translational-modifications control transcriptional responses. Acetylated histone marks as well as some transcriptional factors are recognized by bromodomains (readers). Bromodomain- containing protein (Brd) 4 is a member of the bromodomain and extraterminal (BET) family, which binds to cell type-specific enhancers and promoters. Brd4 has been reported to be essential for enhancer-mediated pro-fibrotic genes expression in many organ fibrosis. However mechanisms of how Brd4 regulates genome-wide pro-fibrotic responses and its interaction with other his acetyltransferase, such as p300, is not clear. Fibrotic responses involve many cellular processes, including epigenetic alterations. Our preliminary data show that by blocking Brd4, multiple profibrotic genes can be downregulated; inhibition of Brd4 can disrupt the association of p300 and H3K27ac with profibrotic genes promoter region. We hypothesis that Brd4 affects chromatin accessibility, mediates the up-regulation of profibrotic genes through interaction with p300 by acetylating active enhancer mark H3K27ac during lung injury and repair process. Our aims are: 1. Determine the effects of Brd4 inhibition on profibrotic responses in lung fibroblasts; 2. Determine if Brd4 through p300 mediates histone acetylation to regulate profibrotic genes expression, 3. Determine the in vivo targeting of Brd4 inhibition in pre-clinical models of lung fibrosis. Results from this research will make a significant impact on our understanding of the role of Brd4 in epigenetic regulation in the pathobiology of IPF.
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