The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)
ALTERNATIVE POLYADENYLATION MODULATES EXPRESSION OF PRO-FIBROTIC PROTEINS AND CONTRIBUTES TO LUNG FIBROSIS
Author ORCID Identifier
Date of Graduation
Biochemistry and Molecular Biology
Doctor of Philosophy (PhD)
Michael R. Blackburn, Ph.D.
Holger Eltzschig, M.D., Ph.D.
Scott E. Evans, M.D.
Leng Han, Ph.D.
Harry Karmouty-Quintana, Ph.D.
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease which affects about 5 to 8 million individuals in the world. Despite the high prevalence, there is currently no cure for IPF, and the cause of this disease is still unclear. Our laboratory and collaborators have shown that nudix hydrolase 21 (NUDT21, which is also known as cleavage factor 25, CFIm25) is a key regulator of alternative polyadenylation (APA). NUDT21 depletion causes 3’UTR shortening via APA leading to enhanced mRNA stability and protein translation. This NUDT21 reduction promotes tumor growth in glioblastoma by enhancing expression of oncogenes. Cancer and IPF share cellular features, such as enhanced expression for pathological mediators and increased cell proliferation. However, whether APA plays a role in lung fibrosis is not known. Our results reveal that NUDT21 reduction is found in lung fibroblasts isolated from IPF patients. Depletion of NUDT21 causes 3’UTR shortening in pro-fibrotic genes, such as Wnt and TGFb1, leading to robust protein expression of the pathological genes and ultimately worsening of pulmonary fibrosis. Additionally, we found that TGFb1 depletes NUDT21 in fibroblasts by transcriptionally inducing miR203 through Smad3. Modulating NUDT21 by overexpression or antagomiR203 attenuated NUDT21 reduction-mediated fibrosis in vitro. The results of this dissertation are significant in that these findings broaden our understanding on the role of APA in fibrosis. The knowledge discovered in this project is potentially beneficial as these results may lead to identification of targets for novel therapies which can halt the progression of IPF.
polyadenylation, pulmonary fibrosis, transforming growth factor β (TGFβ), mRNA, post-transcriptional regulation, alternative polyadenylation, APA, miR203, NUDT21
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