A MUC5B polymorphism associated with Idiopathic Pulmonary Fibrosis mediates overexpression through decreased CpG methylation and C/EBPβ transcriptional activation

Idiopathic pulmonary fibrosis is a progressive and fatal lung disease of unknown aetiology. The strongest genetic risk factor associated with IPF development is a MUC5B promoter polymorphism ( rs35705950 ). However, the mechanism underlying its effects remains unknown. In this study we have focused on the molecular consequences of the polymorphism on the regulation of MUC5B expression. We have identified a combined mechanism involving both methylation and direct transcriptional regulation mediated by the polymorphic variant on MUC5B overexpression. Our results demonstrate that the minor allele (T) associated with rs35705950 disturbs a DNA methylation site, directly increasing MUC5B expression. Furthermore, this same variant also creates a novel binding site for the transcription factor C/EBPβ leading to transcriptional activation of MUC5B . Our findings provide a novel insight into the regulatory effects of the IPF risk allele, rs35705950 and identifies C/EBPβ as an important regulatory factor in the development of IPF.