YTHDF1 deletion in macrophages aggravates LPS-induced inflammation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA998405 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25423000.fastq.gz | Fastqsanger.gz | |||
| SRR25423001.fastq.gz | Fastqsanger.gz | |||
| SRR25423002.fastq.gz | Fastqsanger.gz | |||
| SRR25423003.fastq.gz | Fastqsanger.gz | |||
| SRR25423004.fastq.gz | Fastqsanger.gz |
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Project description:To investigate the effect of YTHDF1 on LPS-induced inflammation, we performed RNA-seq with the total RNA extracted from peritoneal macrophages (PMs) with or without YTHDF1 deletion. Ythdf1-/- or wild type mice were intraperitoneally injected with 6% starch broth. Three days later, PMs were isolated and cultured overnight. Then, the PMs were treated by LPS (1 μg/mL) or PBS for 6 hours, followed by RNA extraction and RNA-seq.
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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:Genipin is a natural blue colorant in food industry. Inflammation is correlated with human disorders, and nuclear factor-κB (NF-κB) is the critical molecule involved in inflammation. In this study, the anti-inflammatory effect of genipin on the lipopolysaccharide (LPS)-induced acute systemic inflammation in mice was evaluated by NF-κB bioluminescence-guided transcriptomic analysis. Transgenic mice carrying the NF-κB-driven luciferase genes were administered intraperitoneally with LPS and various amounts of genipin. Bioluminescent imaging showed that genipin significantly suppressed LPS-induced NF-κB-dependent luminescence in vivo. The suppression of LPS-induced acute inflammation by genipin was further evidenced by the reductions of cytokine levels in sera and organs. Microarray analysis of these organs showed that the transcripts of 79 genes were differentially expressed in both LPS and LPS/genipin groups, and one third of these genes belonged to chemokine ligand, chemokine receptor, and interferon (IFN)-induced protein genes. Moreover, network analysis showed that NF-κB played a critical role in the regulation of genipin-affected gene expression. In conclusion, we newly identified that genipin exhibited anti-inflammatory effects in a model of LPSinduced acute systemic inflammation via downregulation of chemokine ligand, chemokine receptor, and IFN-induced protein productions. A total of 25 transgenic mice (female, 6 to 8 weeks old) were randomly divided into five groups of five mice: (1) mock, no treatment; (2) LPS (4 mg/kg), (3) LPS plus genipin (1 mg/kg), (4) LPS plus genipin (10 mg/kg), and (5) LPS plus genipin (100 mg/kg). Mice were challenged intraperitoneally with LPS and then with genipin 10 min later. Four hours later, mice were imaged for the luciferase activity, and subsequently sacrificed for ex vivo imaging, RNA extraction, and immunohistochemical staining.
2012-02-25 | E-GEOD-35934 | biostudies-arrayexpress
Project description:N6-methyladenosine (m6A) is the most prevalent internal RNA modification in mammalian messenger RNAs (mRNAs). While m6A has been shown to mark groups of mRNAs for coordinated degradation in various physiological processes, the relevance of m6A in affecting translation remains to be determined in intact biological systems in vivo. Here we show that, through its reader protein Ythdf1, m6A promotes a pulse of protein synthesis of target transcripts in response to neuronal stimuli in the adult mouse hippocampus, thereby facilitating learning and memory processes. Mice with genetic deletion of the Ythdf1 gene (Ythdf1-/-) exhibit learning and memory defects, as well as impaired hippocampal synaptic transmission and long-term potentiation (LTP). Selective re-expression of Ythdf1 in the hippocampus of adult Ythdf1-/- mice fully rescues the behavioral and synaptic defects, while hippocampus-specific knockdown of Ythdf1 or Mettl3, the catalytic component of m6A methyltransferase complex, recapitulates the hippocampal deficiency in adult mice. At the molecular level, transcriptome-wide mapping of m6A sites and RNA binding sites of Ythdf1 on hippocampal mRNAs using crosslinking immunoprecipitation followed by high-throughput sequencing (CLIP-seq) uncovered key neuronal genes, including those involved in synaptic transmission and long-term potentiation. Nascent protein labelling and tether reporter assays in cultured hippocampal neurons revealed that Ythdf1 is critical for initiating a pulse of protein synthesis of target transcripts in a neuronal-stimulus-dependent manner. Collectively, our results uncover a pathway of mRNA m6A methylation in learning and memory, which is mediated through Ythdf1 in response to stimuli.
2018-08-17 | GSE106607 | GEO
Project description:Genipin is a natural blue colorant in food industry. Inflammation is correlated with human disorders, and nuclear factor-κB (NF-κB) is the critical molecule involved in inflammation. In this study, the anti-inflammatory effect of genipin on the lipopolysaccharide (LPS)-induced acute systemic inflammation in mice was evaluated by NF-κB bioluminescence-guided transcriptomic analysis. Transgenic mice carrying the NF-κB-driven luciferase genes were administered intraperitoneally with LPS and various amounts of genipin. Bioluminescent imaging showed that genipin significantly suppressed LPS-induced NF-κB-dependent luminescence in vivo. The suppression of LPS-induced acute inflammation by genipin was further evidenced by the reductions of cytokine levels in sera and organs. Microarray analysis of these organs showed that the transcripts of 79 genes were differentially expressed in both LPS and LPS/genipin groups, and one third of these genes belonged to chemokine ligand, chemokine receptor, and interferon (IFN)-induced protein genes. Moreover, network analysis showed that NF-κB played a critical role in the regulation of genipin-affected gene expression. In conclusion, we newly identified that genipin exhibited anti-inflammatory effects in a model of LPSinduced acute systemic inflammation via downregulation of chemokine ligand, chemokine receptor, and IFN-induced protein productions.
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Project description:The RNA N6-methyladenosine (m6A) reader YTHDF1 is implicated in cancer etiology and progression. We discovered that radiotherapy (RT) increased YTHDF1 expression in dendritic cells (DCs) of PBMCs from patients with cancer, but not in other immune cells tested. Elevated YTHDF1 expression in DCs was associated with poor outcomes for patients receiving RT. We found that loss of Ythdf1 in DCs enhanced the antitumor effects of ionizing radiation (IR) by increasing the cross-priming capacity of DCs across multiple murine cancer models. Mechanistically, IR upregulated YTHDF1 expression in DCs through stimulator of IFN genes/type I IFN (STING/IFN-I) signaling. YTHDF1 in turn triggered STING degradation by increasing lysosomal cathepsins, thereby reducing IFN-I production. We created a YTHDF1 deletion/inhibition prototype DC vaccine that significantly improved the therapeutic effect of RT and radioimmunotherapy in a murine melanoma model. Our findings reveal a layer of regulation between YTHDF1/m6A and STING in response to IR, which opens new paths for the development of YTHDF1-targeting therapies.
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Project description:The objective of this study was to investigate the effects of UDCA on J774A.1 cells induced inflammation by LPS. The control group treated with LPS and the UDCA group treated with both LPS and UDCA. Compared with control group, the UDCA group could reduce the inflammation effects in J774A.1 cells.
2023-02-08 | GSE174489 | 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.
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