All ETDs from UAB

Advisory Committee Chair

Jarrod Barnes

Advisory Committee Members

Stefanie Krick

Yan Sanders

Document Type


Date of Award


Degree Name by School

Master of Science (MS) Heersink School of Medicine


Idiopathic pulmonary fibrosis (IPF) is an age-related chronic disease with a me-dian survival period of 3-4 years [1]. Although FDA has approved two drugs that may slow the disease process, there is no effective treatment [2]. IPF is characterized by the excessive deposition of collagen, which leads to deformation of alveolar structure, loss of lung function, and ultimately death [3]. Anti-fibrotic genes such as cyclooxygenase-2 (COX-2) and Heme Oxygenase 1 (HMOX-1) are usually suppressed in the pathogenesis of IPF [4-6], while the mechanisms responsible for the repression of anti-fibrotic genes in IPF are incompletely understood. More evidence has shown that altered epigenetic marks such as histone methylation are involved in silencing anti-fibrosis genes [7]. H3K27Me3 is a key repressive histone mark that mediates gene repression, catalyzed by the methyl-transferase enhancer of Zeste homolog 2 (EZH2) [8]. EZH2 expression is increased in lung fibrosis [9] and its levels/activity is regulated by the post-translational modifications, such as phosphorylation, acetylation, methylation, ubiquitination, sumoylation, and O-GlcNAcylation [10]. In this study, we investigate the effects of O-GlcNAcylation on anti-fibrotic gene expression via the EZH2-H3K27Me3 axis. Our results indicate that O-Glc-NAc levels are increased in IPF lung tissue compared to control human lungs by IHC IV staining and western blots. In primary human lung fibroblasts, inhibition of OGT (O-Glc-NAc transferase) with the OGT inhibitor, OSMI-1, reduced O-GlcNAc levels and EZH2 protein expression as determined by Western blot analysis. In addition, we noticed the significantly increased expression of anti-fibrotic genes, COX-2 and HMOX-1, at the mRNA level in lung fibroblasts with OGT inhibition. Our ChIP assay confirmed that COX-2 and HMOX1 are regulated by H3K27Me3. This indicates that O-GlcNAc can regulate anti-fibrotic genes in lung fibrosis through EZH2-H3K27Me3 axis. Our results support a central role of O-GlcNAc for EZH2-mediated histone hypermethylation in anti-fibrotic genes epigenetic silencing in IPF.



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