Silencing TET1 expression alters the epigenomic landscape and amplifies transcriptomic responses to allergen in airway epithelial cells [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1243303 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32905573_1.fastq.gz | Fastqsanger.gz | |||
| SRR32905573_2.fastq.gz | Fastqsanger.gz | |||
| SRR32905574_1.fastq.gz | Fastqsanger.gz | |||
| SRR32905574_2.fastq.gz | Fastqsanger.gz | |||
| SRR32905575_1.fastq.gz | Fastqsanger.gz |
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Project description:Previous studies have demonstrated that TET1 plays a protective role against house dust mite (HDM)-induced allergic airway inflammation. TET1 transcriptionally responded to HDM extract and regulated the expression of genes involved in asthma in human bronchial epithelial cells (HBECs). How TET1 regulates expression of these genes, however, is unknown. To this end, we measured mRNA expression, DNA methylation, chromatin accessibility and histone modifications in control and TET1 knockdown HBECs treated or untreated with HDM extract. Throughout our analyses of multi-omics data, we detected significant similarities between the effects of TET1 knockdown alone and the effects of HDM treatment alone, all enriched for asthma-related genes and pathways. One especially striking pattern was that both TET1 knockdown and HDM treatment generally led to decreased chromatin accessibility at many of the same genomic loci. Transcription factor enrichment analyses indicated that altered chromatin accessibility following the loss of TET1 may affect, or be affected by, CTCF and CEBP binding. Analysis of H3K27ac levels and comparison with existing datasets suggested a potential impact of TET1 on enhancer activity. TET1 loss also led to changes in DNA methylation, but these changes were generally in regions where accessibility was not changing. Lastly, more significant transcriptomic changes were observed in HBEC cells with TET1 knockdown compared to control cells following HDM challenges. Collectively, our data suggest that TET1 regulates gene expression through distinct mechanisms across various genomic regions in airway epithelial cells, restricting transcriptomic responses to allergen and potentially protecting against the development of asthma.
2025-05-30 | GSE293178 | GEO
Project description:Previous studies have demonstrated that TET1 plays a protective role against house dust mite (HDM)-induced allergic airway inflammation. TET1 transcriptionally responded to HDM extract and regulated the expression of genes involved in asthma in human bronchial epithelial cells (HBECs). How TET1 regulates expression of these genes, however, is unknown. To this end, we measured mRNA expression, DNA methylation, chromatin accessibility and histone modifications in control and TET1 knockdown HBECs treated or untreated with HDM extract. Throughout our analyses of multi-omics data, we detected significant similarities between the effects of TET1 knockdown alone and the effects of HDM treatment alone, all enriched for asthma-related genes and pathways. One especially striking pattern was that both TET1 knockdown and HDM treatment generally led to decreased chromatin accessibility at many of the same genomic loci. Transcription factor enrichment analyses indicated that altered chromatin accessibility following the loss of TET1 may affect, or be affected by, CTCF and CEBP binding. Analysis of H3K27ac levels and comparison with existing datasets suggested a potential impact of TET1 on enhancer activity. TET1 loss also led to changes in DNA methylation, but these changes were generally in regions where accessibility was not changing. Lastly, more significant transcriptomic changes were observed in HBEC cells with TET1 knockdown compared to control cells following HDM challenges. Collectively, our data suggest that TET1 regulates gene expression through distinct mechanisms across various genomic regions in airway epithelial cells, restricting transcriptomic responses to allergen and potentially protecting against the development of asthma.
2025-05-30 | GSE293176 | GEO
Project description:Previous studies have demonstrated that TET1 plays a protective role against house dust mite (HDM)-induced allergic airway inflammation. TET1 transcriptionally responded to HDM extract and regulated the expression of genes involved in asthma in human bronchial epithelial cells (HBECs). How TET1 regulates expression of these genes, however, is unknown. To this end, we measured mRNA expression, DNA methylation, chromatin accessibility and histone modifications in control and TET1 knockdown HBECs treated or untreated with HDM extract. Throughout our analyses of multi-omics data, we detected significant similarities between the effects of TET1 knockdown alone and the effects of HDM treatment alone, all enriched for asthma-related genes and pathways. One especially striking pattern was that both TET1 knockdown and HDM treatment generally led to decreased chromatin accessibility at many of the same genomic loci. Transcription factor enrichment analyses indicated that altered chromatin accessibility following the loss of TET1 may affect, or be affected by, CTCF and CEBP binding. Analysis of H3K27ac levels and comparison with existing datasets suggested a potential impact of TET1 on enhancer activity. TET1 loss also led to changes in DNA methylation, but these changes were generally in regions where accessibility was not changing. Lastly, more significant transcriptomic changes were observed in HBEC cells with TET1 knockdown compared to control cells following HDM challenges. Collectively, our data suggest that TET1 regulates gene expression through distinct mechanisms across various genomic regions in airway epithelial cells, restricting transcriptomic responses to allergen and potentially protecting against the development of asthma.
2025-05-30 | GSE293175 | GEO
Project description:Silencing TET1 expression alters the epigenomic landscape and amplifies transcriptomic responses to allergen in airway epithelial cells
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Project description:Silencing TET1 expression alters the epigenomic landscape and amplifies transcriptomic responses to allergen in airway epithelial cells [ATAC-seq]
| PRJNA1243305 | ENA
Project description:This study has several novel aspects that address molecular mechanisms underlying type 2 immunity and allergic inflammation. We have identified a previously unknown response of human airway epithelial cells to allergens that involves rapid mobilization and release of nuclear DNA (nDNA) from epithelial cells that remain viable throughout the duration of exposure. We show that nDNA release occurs across the apical membrane, but not the basolateral membrane and that sequence analysis of the secreted DNA reveals proportionally higher amounts of promotor and exon sequences and lower intron and intergenic sequences compared to the normal distributions of these regions in the intact genome. Furthermore, unlike DNA release during NETosis, the extracellular DNA is highly fragmented, ranging in size from 1000-5000 bp. We discovered that allergen exposure stimulates caspase 3 by a non-canonical mechanism involving calcium-dependent activation of furin and that caspase 3 activity leads to DNA fragmentation as shown in comet assays. Using a mouse model of allergic inflammation, we demonstrate that allergen-induced type 2 immune responses are markedly reduced by pretreatment with a DNA scavenger and that nDNA release was significantly reduced in mice that were caspase 3 deficient. Moreover, we show that intranasal treatment with mouse genomic DNA combined with submaximal exposure to allergens amplified secretion of Th2 cytokines into bronchoalveolar lavage fluid while DNA alone had no effect. These results highlight a novel, allergen-dependent mechanism of regulated and rapid nDNA mobilization and release that amplifies type 2 immunity in airways and suggests that pharmacotherapies targeting this mechanism may be beneficial in reducing allergic inflammation and exacerbation of asthma.
2022-10-01 | GSE198721 | GEO
Project description:Allergen-induced vital DNA release by the airway epithelium amplifies type-2 immunity
| PRJNA816531 | ENA
Project description:Exaggerated airway constriction triggered by exposure to irritants such as allergen, also called hyperreactivity, is a hallmark of asthma and can be life-threatening. Aside from immune cells, vagal sensory neurons are important for airway hyperreactivity 1-4. However, the identity and signature of the downstream nodes of this adaptive circuit remains poorly understood. Here we show that Dbh+ neurons in the nucleus of the solitary tract (nTS) of the brainstem, and downstream neurons in the nucleus ambiguus (NA), are both necessary and sufficient for chronic allergen-induced airway hyperreactivity. We found that repeated exposures of mice to inhaled allergen activates nTS neurons in a mast cell-, interleukin 4 (IL-4)- and vagal nerve-dependent manner. Single-nucleus RNA-seq followed by RNAscope quantification of the nTS at baseline and following allergen challenges reveals that a Dbh+ population is preferentially activated. Ablation or chemogenetic inactivation of Dbh+ nTS neurons blunted, while chemogenetic activation promoted hyperreactivity. Viral tracing indicates that Dbh+ nTS neurons, capable of producing norepinephrine, project to the NA, and NA neurons are necessary and sufficient to relay allergen signals to postganglionic neurons that then directly drive airway constriction. Focusing on transmitters, delivery of norepinephrine antagonists to the NA blunted allergen-induced hyperreactivity. Together, these findings provide molecular, anatomical and functional definitions of key nodes of a canonical allergen response circuit. The knowledge opens the possibility of targeting neural modulation as an approach to control refractory allergen-induced airway constriction.
2024-04-15 | GSE211538 | GEO
Project description:Exaggerated airway constriction triggered by exposure to irritants such as allergen, also called hyperreactivity, is a hallmark of asthma and can be life-threatening. Aside from immune cells, vagal sensory neurons are important for airway hyperreactivity 1-4. However, the identity and signature of the downstream nodes of this adaptive circuit remains poorly understood. Here we show that Dbh+ neurons in the nucleus of the solitary tract (nTS) of the brainstem, and downstream neurons in the nucleus ambiguus (NA), are both necessary and sufficient for chronic allergen-induced airway hyperreactivity. We found that repeated exposures of mice to inhaled allergen activates nTS neurons in a mast cell-, interleukin 4 (IL-4)- and vagal nerve-dependent manner. Single-nucleus RNA-seq followed by RNAscope quantification of the nTS at baseline and following allergen challenges reveals that a Dbh+ population is preferentially activated. Ablation or chemogenetic inactivation of Dbh+ nTS neurons blunted, while chemogenetic activation promoted hyperreactivity. Viral tracing indicates that Dbh+ nTS neurons, capable of producing norepinephrine, project to the NA, and NA neurons are necessary and sufficient to relay allergen signals to postganglionic neurons that then directly drive airway constriction. Focusing on transmitters, delivery of norepinephrine antagonists to the NA blunted allergen-induced hyperreactivity. Together, these findings provide molecular, anatomical and functional definitions of key nodes of a canonical allergen response circuit. The knowledge opens the possibility of targeting neural modulation as an approach to control allergen-induced airway constriction.
2024-04-15 | GSE200003 | GEO
Project description:Allergen exposure induces the airway epithelium to produce chemoattractants, proallergic interleukins, matrix-modifying proteins, and proteins that influence the growth and activation state of airway structural cells. These proteins, in turn, contribute to the influx of inflammatory cells and changes in structure that characterize the asthmatic airway. To use the response of the airway epithelium to allergen to identify genes not previously associated with allergic responses, we compared gene expression in cytokeratin-positive cells before and after segmental allergen challenge. After challenge with concentrations of allergen in the clinically relevant range, 755 (6%) of the detectable sequences had geometric mean fold-changes in expression, with 95% confidence intervals that excluded unity. Using a prospectively defined conservative filtering algorithm, we identified 141 sequences as upregulated and eight as downregulated, with confirmation by conventional polymerase chain reaction in all 10 sequences studied. Using this approach, we identified asthma-associated sequences including interleukin (IL-)-3, IL-4, and IL-5 receptor subunits, the p65 component of nuclear factor-kappaB, and lipocortin. The genomic response of the human airway to concentrations of allergen in the clinically relevant range involves a greater number of genes than previously recognized, including many not previously associated with asthma that are differentially expressed after airway allergen exposure. Keywords: Before and after allergen challenge
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