The IPF-associated variant in MUC5B, rs35705950, resides within an enhancer that is subject to lineage- and disease-dependent epigenetic remodeling

Genetic polymorphisms account for over 30% of the risk for sporadic pulmonary fibrosis. Yet it remains unknown how the minor variant of rs35705950, the strongest driver of IPF genetic risk, mediates molecular changes to influence IPF development. In the parent publication we use chromatin immunoprecipitation, nuclease sensitivity, nascent transcript analysis, bulk RNA- and ATAC-seq from established cell lines, and finally, paired single-nucleus RNA- and ATAC-seq from IPF patients and controls to demonstrate that the variant rs35705950 resides within a classically defined enhancer of the MUC5B locus. In this pilot study we used paired single nucleus RNA- and ATAC-sequencing on fresh frozen control and IPF lung tissue specimens obtaind through the Lung Transplant Research Consortium or our Systems Biology project (COMIRB #15-1147). Samples were stratified by rs35705950 genotype and IPF disease status and include 2 control specimens (1 homozygous nonvariant at rs35705950 (GG), one homozygous variant (TT)), and 2 IPF specimens (1 homozygous nonvariant at rs35705950 (GG), one homozygous variant (TT)). To minimize confounding variability with small sample size samples were age-, race-, and sex-matched. **Unable to provide raw sequencing files due to conflict with privacy protection for human subjects**