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Citation Information: JCI Insight. 2021;6(2):e144294. https://doi.org/10.1172/jci.insight.144294.
Abstract
The G/T transversion rs35705950, located approximately 3 kb upstream of the MUC5B start site, is the cardinal risk factor for idiopathic pulmonary fibrosis (IPF). Here, we investigate the function and chromatin structure of this –3 kb region and provide evidence that it functions as a classically defined enhancer subject to epigenetic programming. We use nascent transcript analysis to show that RNA polymerase II loads within 10 bp of the G/T transversion site, definitively establishing enhancer function for the region. By integrating Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analysis of fresh and cultured human airway epithelial cells with nuclease sensitivity data, we demonstrate that this region is in accessible chromatin that affects the expression of MUC5B. Through applying paired single-nucleus RNA- and ATAC-seq to frozen tissue from IPF lungs, we extend these findings directly to disease, with results indicating that epigenetic programming of the –3 kb enhancer in IPF occurs in both MUC5B-expressing and nonexpressing lineages. In aggregate, our results indicate that the MUC5B-associated variant rs35705950 resides within an enhancer that is subject to epigenetic remodeling and contributes to pathologic misexpression in IPF.
Authors
Fabienne Gally, Sarah K. Sasse, Jonathan S. Kurche, Margaret A. Gruca, Jonathan H. Cardwell, Tsukasa Okamoto, Hong W. Chu, Xiaomeng Hou, Olivier B. Poirion, Justin Buchanan, Sebastian Preissl, Bing Ren, Sean P. Colgan, Robin D. Dowell, Ivana V. Yang, David A. Schwartz, Anthony N. Gerber
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