YTHDF1-CLOCK axis contributes to pathogenesis of allergic airway inflammation through LLPS [mRNA-seq]
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PROVIDER: PRJNA1079998 | ENA |
REPOSITORIES: ENA
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Project description:N6-methyladenosine (m6A) modification has been implicated in many cell processes and diseases. YTHDF1, a translation-facilitating m6A reader, is not previously shown to be related to allergic airway inflammation. Here, we report that YTHDF1 is highly expressed in allergic airway epithelial cells (AECs) and asthmatic patients, and influences proinflammatory responses. CLOCK, a subunit of the circadian clock pathway, is the direct target of YTHDF1. YTHDF1 augments CLOCK translation in an m6A-dependent manner. Allergens enhance the liquid‒liquid phase separation (LLPS) of YTHDF1 and drive the formation of a complex comprising dimeric YTHDF1 and CLOCK mRNA, which is distributed to stress granules (SGs). Moreover, YTHDF1 strongly activates NLRP3 inflammasome production and IL-1β secretion, leading to airway inflammatory responses, but these phenotypes are abolished by deleting CLOCK. These findings demonstrate that YTHDF1 is an important regulator of asthmatic airway inflammation, suggesting a potential therapeutic target for allergic airway inflammation.
2024-03-15 | GSE256531 | GEO
Project description:N6-methyladenosine (m6A) modification has been implicated in many cell processes and diseases. YTHDF1, a translation-facilitating m6A reader, is not previously shown to be related to allergic airway inflammation. Here, we report that YTHDF1 is highly expressed in allergic airway epithelial cells (AECs) and asthmatic patients, and influences proinflammatory responses. CLOCK, a subunit of the circadian clock pathway, is the direct target of YTHDF1. YTHDF1 augments CLOCK translation in an m6A-dependent manner. Allergens enhance the liquid‒liquid phase separation (LLPS) of YTHDF1 and drive the formation of a complex comprising dimeric YTHDF1 and CLOCK mRNA, which is distributed to stress granules (SGs). Moreover, YTHDF1 strongly activates NLRP3 inflammasome production and IL-1β secretion, leading to airway inflammatory responses, but these phenotypes are abolished by deleting CLOCK. These findings demonstrate that YTHDF1 is an important regulator of asthmatic airway inflammation, suggesting a potential therapeutic target for allergic airway inflammation.
2024-03-15 | GSE256458 | GEO
Project description:YTHDF1-CLOCK axis contributes to pathogenesis of allergic airway inflammation through LLPS [m6A-seq]
| PRJNA1079717 | ENA
Project description:Obesity is associated with severe, difficult to control asthma, and increased airway oxidative stress. Mitochondrial reactive oxygen species (mROS) are an important source of oxidative stress leading us to hypothesize that targeting mROS in obese allergic asthma might be an effective treatment strategy. Using a mouse model of house dust mite (HDM) induced allergic airway disease in mice fed a low- (LFD) or high-fat diet (HFD), and the mitochondrial antioxidant MitoQuinone (MitoQ); we investigated the effects of obesity and mROS on airway inflammation, remodelling and airway hyperreactivity (AHR). HDM induces airway inflammation, remodelling and hyperreactivity in both lean and obese mice. Obese allergic mice showed increased lung tissue eotaxin levels, airway tissue eosinophilia and AHR when compared to lean allergic mice. MitoQ reduced markers of airway inflammation, remodelling and hyperreactivity in both lean and obese allergic mice, and tissue eosinophilia in obeseHDM mice. mROS regulates cell signalling by protein oxidation of multiple downstream targets: MitoQ reduced HDM-induced cysteine-sulfenylation of several proteins including those involved in the unfolded protein response (UPR). In summary, mROS mediates the development of allergic airway disease and hence MitoQ might be effective for the treatment for asthma, and specific features of obese asthma.
2023-06-02 | PXD029715 | Pride
Project description:Signaling via the arylhydrocarbon receptor (AhR) is thought to contribute to exacerbation of allergic asthma by anthropogenic pollution. The physiological role of AhR and its downstream targets CYP1 family members upon exposure to aeroallergens remain unknown. We seek to characterize the role of the AhR pathway for the regulation of allergic airway inflammation (AAI). We employed knockout animals of the AhR and its downstream target cytochrome P450 enzymes CYP1A1, CYP1A2 and CYP1B1 and subjected them to preclinical allergic asthma models (ragweed and house dust mite) to assess the role of AhR and CYP1 family members in allergic airway inflammation. Histological, transcriptional and functional assays were used to uncover relevant cell types and mechanistic insights. In the ragweed model, AhRKO/KO and CYP1B1KO/KO but not CYP1A2 KO/KO or CYP1A2KO/KO animals showed exacerbation of AAI including elevated infiltration of cells in the bronchoalveolar lavage fluid and increased serum levels of IgE and allergen-specific IgG1. AhR KO/KO and CYP1B1KO/KO animals showed also more severe reactions in HDM-induced allergic AAI. Bone marrow chimeras as well as qPCR analysis and immune fluorescence histology indicate that expression of CYP1B1 in non-hematopoietic cells – presumably lung epithelial cells – is necessary to prevent exacerbation of HDM-induced AAI. Mechanistically, we show that CYP1B1 deficiency leads to enhanced expression and activity of CYP1A1 in lung epithelial cells and thus potentially to deprivation from endogenous AhR ligands. Transcriptional analysis of primary lung epithelial cells indicates a functional link of the AhR to regulation of circadian clock genes at baseline and massive alteration of gene expression upon allergen exposure.
2022-05-23 | GSE158715 | GEO
Project description:In the first decade of life, high-asthma risk urban children develop stable phenotypes of respiratory health versus disease that link early life environmental exposures to childhood allergic sensitization and asthma. Moreover, unique patterns of nasal gene expression demonstrate how specific molecular pathways underlie distinct respiratory phenotypes, including allergic and non-allergic asthma.
2021-04-01 | GSE145505 | GEO
Project description:N6-methyladenosine (m6A) governs the fate of RNAs through m6A readers. Colorectal cancer (CRC) exhibits aberrant m6A modifications and expression of m6A regulators. However, little is known about how m6A readers interpret oncogenic m6A methylome for malignant transformation. m6A reader YTHDF1 was overexpressed by copy number gain/amplification in majority of CRCs. YTHDF1 high expression and CNVs predict increased risk of CRC relapse. Transcriptome profiles of YTHDF1-high tumors exhibit highly metastatic features. YTHDF1 promoted CRC tumor cell and organoid proliferation and enhanced metastasis. Ythdf1 knockout dampened tumor growth in carcinogen-induced CRC model. Through multiomic integration, RhoA activator ARHGEF2 was characterized as the key functional YTHDF1 target based on its m6A and YTHDF1-binding signal, translation efficiency changes, protein correlations with YTHDF1 in clinical samples, and disrupted RhoA features by YTHDF1 knockdown. Moreover, YTHDF1-ARHGEF2 co-regulation was observed in YTHDF1-overexpressing metastatic sites and carcinogen-induced Ythdf1-null CRC tumors. ARHGEF2 overexpression significantly rescued RhoA signaling, tumor cell survival and invasiveness impaired by YTHDF1 knockdown both in vitro and in vivo, further confirming the essential function of ARHGEF2.
2022-01-18 | GSE159425 | GEO
Project description:Translation activation of local synaptic mRNA is critical to learning and memory. Despite extensive studies on how phosphorylations of ribosome units and translation factors enable fast response to exogenous stimuli, our knowledge on molecular pathways utilized by RNA binding proteins (RBPs) to control translation of specific mRNAs remains incomplete. We have previously found that YTHDF1 regulates depolarization-induced protein synthesis by promoting translation of N6-methyladenosine (m6A)-modified transcripts. Here we report an unexpected mechanism that the stimuli-induced neuronal translation is mediated by phosphorylation of a YTHDF1-binding protein FMRP. Phosphorylation of FMRP serine 499 induced by neuronal depolarization alters the condensing behavior of prion-like protein YTHDF1. Unphosphorylated FMRP sequesters YTHDF1 away from the translation initiation complex, whereas the stimulation-induced FMRP phosphorylation releases YTHDF1 to form translational active condensates with the ribosome to activate translation of YTHDF1 target transcripts. In fragile X syndrome (FXS) models characterized with low FMRP expression, we observed YTHDF1-mediated hyperactive translation, which notably impacts FXS pathophysiology. Developmental defects in an FXS forebrain organoid model could be reversed by a selective small-molecule inhibitor of YTHDF1 which acts by suppressing its condensation in neurons. We characterized transcriptome-wide translation alterations with the inhibitor treatment in organoids and identified targets that explain alleviated FXS pathology. Our study thus reveals FMRP and its phosphorylation as an important regulator of the activity-dependent translation during neuronal development and stimulation, and identifies YTHDF1 as a potential therapeutic target for FXS in which developmental defects caused by FMRP depletion could be reversed through YTHDF1 inhibition.
2023-10-31 | GSE214882 | GEO
Project description:Background: A specific subset of regulatory IL-10 producing B cells has been extensively studied in autoimmune and inflammatory pathologies. These cells are able to constrain exacerbated inflammation by inhibiting T cell mediated responses and maturation of antigen presenting cells. In allergic diseases, observations that increase of regulatory B cells is necessary for allergen tolerance suggest that development of allergic asthma would be associated with a defect in the regulatory B cells compartment. Objective: We sought to (i) characterize regulatory IL-10+ regulatory B cell subset in Balb/c mice by microarray and flow cytometry and (ii) investigate their regulatory capacity in vivo in a house dust mite model of allergic asthma. Results: We identified an IL-10 producing B cells subset able to control T cell proliferation in vitro in both control and asthmatic mice. This subset is decreased in allergic mice. IL-10+ Breg cells express high levels of CD9 and upregulate CD70 and CD73 after activation. Expression of CD9 allows identifying more than 50% of Bregs. Interestingly CD9+ B cells inhibit TH2-TH17 allergic airway inflammation in vivo after adoptive transfer in an IL-10 dependent manner. Conclusions: Herein, we demonstrate that induction of allergic asthma dampens the generation of Bregs contributing to exacerbated airway inflammation. We identified a distinct CD9+ Breg-cell population decreased in lung of HDM mice and able to control asthma and allergic airway inflammation by producing IL-10 after adoptive transfer. This study points B cells as an interesting therapeutic target in allergic asthma. IL-10+ B cells (n=3) and 3 IL-10- B cells (n=3) in control mice + IL-10+ B cells (n=3) and 3 IL-10- B cells (n=3) from asthmatic allergic (HDM) mice
2015-03-01 | E-GEOD-57772 | biostudies-arrayexpress
Project description:Background: Inhalation exposure to biological particulate matter (BioPM) from livestock farms may provoke exacerbations in subjects suffering from allergy and asthma. The aim of this study was to use a murine model of allergic asthma to determine the effect of BioPM derived from goat farm on airway allergic responses Methods: Fine (< 2.5 μm) BioPM was collected from an indoor goat stable. Female BALB/c mice were ovalbumin (OVA) sensitized and challenged with OVA or saline as control. The OVA and saline groups were divided in sub-groups and exposed intranasally to different concentrations (0, 0.9, 3, or 9 μg) of goat farm BioPM. Bronchoalveolar lavage fluid (BALF), blood and lung tissues were collected. Results: In saline-challenged mice, goat farm BioPM alone induced a dose-dependent increase in neutrophils in BALF and induced production of macrophage inflammatory protein-3a). In OVA-challenged mice, BioPM significantly enhanced 1) inflammatory cells in BALF, 2) OVA-specific Immunoglobulin (Ig)G1, 3) interleukin-23 production, 4) airway mucus secretion-specific gene expression. RNAseq analysis of lungs indicates that neutrophil chemotaxis and oxidation-reduction processes were the representative genomic pathways in saline and OVA-challenged mice, respectively. Conclusions: A single exposure to goat farm BioPM enhanced airway inflammation in both saline and OVA-challenged allergic mice, with neutrophilic response as Th17 disorder and eosinophilic response as Th2 disorder indicative of the severity of allergic responses. Identification of the mode of action by which farm PM interacts with airway allergic pathways will be useful to design potential therapeutic approaches.
2020-08-01 | GSE148240 | GEO