Genome-wide profiling of an enhancer-associated histone modification reveals the influence of asthma on the epigenome of the airway epithelium.
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ABSTRACT:
PROVIDER: PRJNA432248 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6653400.fastq.gz | Fastqsanger.gz | |||
| SRR6653391.fastq.gz | Fastqsanger.gz | |||
| SRR6653401.fastq.gz | Fastqsanger.gz | |||
| SRR6653392.fastq.gz | Fastqsanger.gz | |||
| SRR6653402.fastq.gz | Fastqsanger.gz |
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Project description:Asthma is a chronic inflammatory disease of the airways driven by complex genetic-environmental interactions. Epigenomic mechanisms including histone modifications and DNA methylation are altered in key cell types of asthma. However, genome-wide studies of histone modifications in the airway epithelium of asthmatics have yet to be undertaken. We undertook genome-wide profiling of an enhancer (regulatory domain)-associated histone modification H3K27ac in bronchial epithelial cells (BECs) from asthmatic and healthy control individuals. We identified 49,903 (P<0.05) regions exhibiting differential H3K27ac enrichment in asthma and found they clustered predominately at genes associated with Th2-high asthma (e.g. CLCA1) and epithelial processes (e.g. EMT). We determined asthma had a dramatic influence on the enhancer landscape of BECs and identified asthma-associated Super-Enhancers encompassing genes encoding transcription factors (e.g. TP63) and enzymes involved in lipid metabolism (e.g. NOX4). We integrated published protein expression, epigenomic and transcriptomic datasets and identified epithelium-specific transcription factors associated with H3K27ac in asthma (e.g. TP73) and dynamic relationships between asthma-associated changes in H3K27ac, DNA methylation, genetic susceptibility and transcriptional profiles. Finally, using a CRISPR-based approach to recapitulate the H3K27ac landscape of asthma in vitro, we provide proof of principal that asthma-associated gene expression (e.g. SERPINB2) is driven in part by aberrant histone acetylation. This report identifies the influence of asthma on the epigenome of airway epithelium and provides evidence that aberrant epigenomic mechanisms exert functional consequences in key cell types of asthma, validating the combination of genome-wide and epigenome-editing approaches in identifying and deciphering the molecular mechanisms underlying asthma pathogenesis.
2019-06-04 | GSE109894 | GEO
Project description:We performed genome-wide profiling of miRNA expression in the airway epithelial compartment in asthma to identify miRNA pathways associated with epithelial abnormalities using miRNA microarrays and real-time PCR. We also sought to identify the effect of inhaled corticosteroids (ICS) on airway epithelial miRNA expression Samples were obtained from airway epithelial cells by bronchoscopic brushing from three groups of subjects: Healthy Controls ( N=12), Steroid Naïve Asthma (N=16), Steroid-requiring Asthma (N=19).
2012-12-05 | E-GEOD-34466 | biostudies-arrayexpress
Project description:Although childhood asthma is in part an airway epithelial disorder, the development of the airway epithelium in asthma is not understood. We sought to characterize airway epithelial developmental phenotypes in those with and without recurrent wheeze and the impact of infant infection with respiratory syncytial virus (RSV). Nasal airway epithelial cells (NAECs) were collected at age 2-3 years from an a priori designed nested birth cohort of children from four mutually exclusive groups of wheezers/non-wheezers and RSV-infected/uninfected in the first year of life. NAECs were cultured in air-liquid interface differentiation conditions followed by a combined analysis of single cell RNA sequencing (scRNA-seq) and in vitro infection with respiratory syncytial virus (RSV). NAECs from children with a wheeze phenotype were characterized by abnormal differentiation and basal cell activation of developmental pathways, plasticity in precursor differentiation and a delayed onset of maturation. NAECs from children with wheeze also had increased diversity of currently known RSV receptors and blunted anti-viral immune responses to in vitro infection. The most dramatic changes in differentiation of cultured epithelium were observed in NAECs derived from children that had both wheeze and RSV in the first year of life. Together this suggests that airway epithelium in children with wheeze is developmentally reprogrammed and characterized by increased barrier permeability, decreased antiviral response, and increased RSV receptors, which may predispose to and amplify the effects of RSV infection in infancy and susceptibility to other asthma risk factors that interact with the airway mucosa.
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Project description:Rhinovirus infections are the most common cause of asthma exacerbations. The complex responses by the airway epithelium to rhinovirus can be captured by gene expression profiling. We hypothesized that the upper and lower airway epithelium exhibit differential responses to double-stranded RNA (dsRNA), and that this is modulated by the presence of asthma and allergic rhinitis. Identification of dsRNA-induced gene expression profiles by microarray of primary nasal and bronchial epithelial cells from the same individuals and examining the impact of allergic rhinitis with and without concomitant allergic asthma on expression profiles. 17 subjects were included in a cross-sectional study (6 allergic asthma and allergic rhinitis; 5 allergic rhinitis; 6 healthy controls). RNA was extracted from isolated and cultured epithelial cells that were stimulated with Poly(I:C) for 24 hours from bronchial brushes and nasal biopsies, and analyzed by microarray (Affymetrix U133+ PM Genechip Array).
2013-10-18 | E-GEOD-51392 | biostudies-arrayexpress
Project description:BackgroundAsthma is a chronic airway disease driven by complex genetic-environmental interactions. The role of epigenetic modifications in bronchial epithelial cells (BECs) in asthma is poorly understood.MethodsWe piloted genome-wide profiling of the enhancer-associated histone modification H3K27ac in BECs from people with asthma (n = 4) and healthy controls (n = 3).ResultsWe identified n = 4,321 (FDR < 0.05) regions exhibiting differential H3K27ac enrichment between asthma and health, clustering at genes associated predominately with epithelial processes (EMT). We identified initial evidence of asthma-associated Super-Enhancers encompassing genes encoding transcription factors (TP63) and enzymes regulating lipid metabolism (PTGS1). We integrated published datasets to identify epithelium-specific transcription factors associated with H3K27ac in asthma (TP73) and identify initial relationships between asthma-associated changes in H3K27ac and transcriptional profiles. Finally, we investigated the potential of CRISPR-based approaches to functionally evaluate H3K27ac-asthma landscape in vitro by identifying guide-RNAs capable of targeting acetylation to asthma DERs and inducing gene expression (TLR3).ConclusionOur small pilot study validates genome-wide approaches for deciphering epigenetic mechanisms underlying asthma pathogenesis in the airways.
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Project description:We performed genome-wide profiling of miRNA expression in the airway epithelial compartment in asthma to identify miRNA pathways associated with epithelial abnormalities using miRNA microarrays and real-time PCR. We also sought to identify the effect of inhaled corticosteroids (ICS) on airway epithelial miRNA expression
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Project description:Group 2 innate lymphoid (ILC2) cells are major producers of the cytokines that drive allergic asthma and elevated levels of ILC2s have been detected in the blood and sputum of asthma patients. Asthma susceptibility has strong (epi)genetic components, but the underlying mechanisms and whether they are linked to ILC2 biology remain unclear. To reveal the molecular basis of ILC2 function in allergic airway inflammation (AAI) and assess its relevance for understanding how genetic variation affects asthma susceptibility. Gata3-IRES-YFP reporter mice were used to isolate ILC2s from bronchoalveolar lavage fluid and lymph nodes. Human naive ILC2s were purified from peripheral blood and activated in vitro. We employed RNA-Seq, ChIPm-Seq and computational approaches to study the transcriptome and epigenome in the context of ILC2 activation, tissue-specific functions and genetic susceptibility to asthma. Activated ILC2s displayed a tissue-specific gene expression signature that emerged from a highly similar epigenome. We identify superenhancers - a class of regulatory regions susceptible to epigenetic drugs - controlling ILC2 identity and asthma-associated genes. The majority of genes implicated in asthma by genome-wide association studies resided in an active or primed state in ILC2s. A substantial number of asthma-associated genetic variants were found in ILC2 gene regulatory elements. Our genome-wide analyses reveal new potential functions for ILC2s in AAI, which possess a plastic and flexible epigenome. Importantly, we reveal a strong link between gene regulatory mechanisms in ILC2s and the (epi)genetic basis of asthma susceptibility, supporting a pathogenic role for ILC2s in human asthma.
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