Dissecting the regulatory role for a MUC5B polymorphism involved in Idiopathic Pulmonary Fibrosis

• Main Author: Armesto Jimenez, Amaranta
• Other Authors: Magnús Karl Magnússon, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland
• Format: Doctoral or Postdoctoral Thesis
• Language: English
• Published: University of Iceland, School of Health Sciences, Faculty of Medicine 2018
• Subjects: CEBPB; Idiopathic pulmonary fibrosis; Methylation; MUC5B; polymorphism; rs35705950 polymorphism; Lungnasjúkdómar; Stökkbreytingar; Erfðabreytileiki; Doktorsritgerðir; Iceland
• Online Access: https://hdl.handle.net/20.500.11815/764

Thesis for a doctoral degree at the University of Iceland Idiopathic pulmonary fibrosis is a severe lung disease with unknown aetiology. The lifespan is approximately 3 to 5 years after diagnosis, and the treatments available such as lung transplant are high risk and are not suitable for all patients. In recent years, new drugs such as pirferidone and nintedanib have proved to slow down IPF progression by targeting profibrotic signaling pathways. However, IPF is usually detected in advanced stages, diminishing the beneficial effect of new treatments. Therefore, to find novel risk factors and preclinical characteristics of IPF has become an important task in the field. A recent genome wide association study (GWAS) performed in IPF patients compared to controls revealed a common MUC5B cis-regulatory region polymorphism (rs35705950), where a G is replaced by a T allele in around 45% of IPF patient compared to an 11% allele frequency in controls. This polymorphism has become the strongest risk factor (genetic and otherwise) associated with IPF. Furthermore, the presence of the minor T allele has been associated to subclinical lung fibrosis, suggesting an important role of the MUC5B polymorphism early in IPF development. However, the mechanism underlying the effect of the MUC5B cis-regulatory polymorphism remains unknown. In this study we have focused on the molecular consequences of the polymorphism on the regulation of MUC5B expression in human bronchial epithelial cells. The results shown in this project corroborate the gain of function role of the minor T allele. Also, we have identified a combined mechanism involving both methylation and direct transcriptional regulation mediated by the polymorphic variant on MUC5B overexpression. On the one hand, the minor T allele destroys a CpG methylation site, previously associated with MUC5B inhibition. On the other hand, the replacement of the wild type G allele with a T allele generates a novel C/EBPβ activating transcription binding site. Using two different approach ...