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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE157691 | GEO | 2020/12/29

REPOSITORIES: GEO

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Gain-of-function MUC5B Promoter Variant, Strongly Linked to Idiopathic Pulmonary Fibrosis, Defines an Epigenetically Poised Enhancer (ATAC-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 | GSE157606 | GEO

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

2020-12-29 | GSE156541 | GEO

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

Project description:Gain-of-function MUC5B Promoter Variant, Strongly Linked to Idiopathic Pulmonary Fibrosis, Defines an Epigenetically Poised Enhancer

| PRJNA662469 | ENA

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

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

| PRJNA658315 | ENA

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

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

| PRJNA662222 | ENA

MUC5B Promoter Variant rs35705950 Affects MUC5B Expression in the Distal Airways in Idiopathic Pulmonary Fibrosis.

Project description: Not available

| S-EPMC4803086 | biostudies-literature

A variant in the promoter of MUC5B and idiopathic pulmonary fibrosis.

Project description: Not available

| S-EPMC4327944 | biostudies-literature

MUC5B and Idiopathic Pulmonary Fibrosis.

Project description:Idiopathic pulmonary fibrosis (IPF), a fatal disease that is a result of complex interactions between genetics and the environment, has limited treatment options. We have identified the MUC5B promoter polymorphism and other common genetic variants that in aggregate explain roughly one-third of disease risk. The MUC5B promoter polymorphism is the strongest and the most replicated genetic risk factor for IPF, appears to be protective and predictive in this disease, and is likely involved in disease pathogenesis through an increase in MUC5B expression in terminal bronchi and honeycombed cysts. Expression of MUC5B is also highly correlated with expression of cilium genes in IPF lung. Our work suggests that mucociliary dysfunction in the distal airway may play a role in the development of progressive fibroproliferative lung disease. In addition, our work has important implications for secondary prevention, early detection, and future early and personalized treatment based on genetic profiles.

| S-EPMC4722833 | biostudies-literature

XBP1S Regulates MUC5B in a Promoter Variant-Dependent Pathway in Idiopathic Pulmonary Fibrosis Airway Epithelia.

Project description:Rationale: The goal was to connect elements of idiopathic pulmonary fibrosis (IPF) pathogenesis, including chronic endoplasmic reticulum stress in respiratory epithelia associated with injury/inflammation and remodeling, distal airway mucus obstruction and honeycomb cyst formation with accumulation of MUC5B (mucin 5B), and associations between IPF risk and polymorphisms in the MUC5B promoter. Objectives: To test whether the endoplasmic reticulum (ER) stress sensor protein ERN2 (ER-to-nucleus signaling 2) and its downstream effector, the spliced form of XBP1S (X-box-binding protein 1), regulate MUC5B expression and differentially activate the MUC5B promoter variant in respiratory epithelia. Methods: Primary human airway epithelial (HAE) cells, transgenic mouse models, human IPF lung tissues, and cell lines expressing XBP1S and MUC5B promoters were used to explore relationships between the ERN2/XBP1S pathway and MUC5B. An inhibitor of the pathway, KIRA6, and XBP1 CRISPR-Cas9 were used in HAE cells to explore therapeutic potential. Measurements and Main Results: ERN2 regulated MUC5B and MUC5AC mRNAs. Downstream XBP1S selectively promoted MUC5B expression in vitro and in distal murine airway epithelia in vivo. XBP1S bound to the proximal region of the MUC5B promoter and differentially upregulated MUC5B expression in the context of the MUC5B promoter rs35705950 variant. High levels of ERN2 and XBP1S were associated with excessive MUC5B mRNAs in distal airways of human IPF lungs. Cytokine-induced MUC5B expression in HAE cells was inhibited by KIRA6 and XBP1 CRISPR-Cas9. Conclusions: A positive feedback bistable ERN2-XBP1S pathway regulates MUC5B-dominated mucus obstruction in IPF, providing an unfolded protein response-dependent mechanism linking the MUC5B promoter rs35705950 polymorphism with IPF pathogenesis. Inhibiting ERN2-dependent pathways/elements may provide a therapeutic option for IPF.

| S-EPMC6635783 | biostudies-literature

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis.

Project description:The gain-of-function mucin 5B (MUC5B) promoter variant, rs35705950, confers the largest risk, genetic or otherwise, for the development of idiopathic pulmonary fibrosis; however, the mechanisms underlying the regulation of MUC5B expression have yet to be elucidated. Here, we identify a critical regulatory domain that contains the MUC5B promoter variant and has a highly conserved forkhead box protein A2 (FOXA2) binding motif. This region is differentially methylated in association with idiopathic pulmonary fibrosis, MUC5B expression, and rs35705950. In addition, we show that this locus binds FOXA2 dynamically, and that binding of FOXA2 is necessary for enhanced expression of MUC5B. In aggregate, our findings identify novel targets to regulate the expression of MUC5B.

| S-EPMC5516283 | biostudies-literature

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