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

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

PROVIDER: PRJNA679078 | ENA |

REPOSITORIES: ENA

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

Project description: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.

2020-12-29 | GSE161685 | GEO

Gain-of-function MUC5B Promoter Variant, Strongly Linked to Idiopathic Pulmonary Fibrosis, Defines an Epigenetically Poised Enhancer (PRO-seq)

Project description:The G/T transversion, rs35705950, located approximately 3 kb upstream of the MUC5B start site, is the cardinal risk factor for 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 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 non-expressing 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.

2020-12-29 | GSE156541 | GEO

Gain-of-function MUC5B Promoter Variant, Strongly Linked to Idiopathic Pulmonary Fibrosis, Defines an Epigenetically Poised Enhancer (ATAC-seq)

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The MUC5B IPF risk variant promotes a distal airway secretory phenotype and loss of alveolar markers

Project description:The dominant risk factor for the development of idiopathic pulmonary fibrosis (IPF) is a common variant in the promoter region of the airway mucin MUC5B, variant rs35705950. The MUC5B promoter variant enhances MUC5B expression in the terminal respiratory bronchiole, where it is normally absent. We pursued a spatial gene expression approach to understand how the MUC5B variant influences IPF in age-matched unaffected and IPF lung tissue specimens.

2024-07-29 | GSE267521 | GEO

The MUC5B-associated variant rs35705950 resides within an enhancer subject to lineage- and disease-dependent epigenetic remodeling.

Project description: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.

| S-EPMC7934873 | biostudies-literature

The MUC5B IPF risk variant promotes a distal airway secretory phenotype and loss of alveolar markers

Project description:The MUC5B IPF risk variant promotes a distal airway secretory phenotype and loss of alveolar markers

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Human IPF and control lungs LC-MSMS

Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by patchy scarring of the distal lung with limited therapeutic options and poor prognosis. Here, we show that conditional deletion of the ubiquitin ligase Nedd4-2 in lung epithelial cells in adult mice produces chronic lung disease that shares key features with IPF including progressive fibrosis and bronchiolization with increased expression of Muc5b in peripheral airways, honeycombing and characteristic alterations in the lung proteome

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A hPSC system for characterizing MUC5B-expressing airway epithelia

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