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Myeloid Zfhx3 Deficiency Protects Against Influenza A Virus-induced Lung Injury and Mortality Increased by Hypercapnia

ABSTRACT: Myeloid Zfhx3 Deficiency Protects Against Influenza A Virus-induced Lung Injury and Mortality Increased by Hypercapnia

PROVIDER: PRJNA1020822 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26164315.fastq.gz	Fastqsanger.gz
	SRR26164316.fastq.gz	Fastqsanger.gz
	SRR26164317.fastq.gz	Fastqsanger.gz
	SRR26164318.fastq.gz	Fastqsanger.gz
	SRR26164319.fastq.gz	Fastqsanger.gz

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Myeloid Zfhx3 Deficiency Protects Against Influenza A Virus-induced Lung Injury and Mortality Increased by Hypercapnia

Project description:Zfhx3, human ortholog of the Drosophila Zfh2 and first known mediator of hypercapnic immune suppression in vivo, is expressed in human and mouse MØs and its myeloid deletion reversed the effects of hypercapnia in gene expression in murine alveolar macrophages and protects against influenza A virus proliferation, lung injury and mortality increased by hypercapnia in infected mice.

2024-01-21 | GSE243969 | GEO

Myeloid Zfhx3 Deficiency Protects Against Hypercapnia-induced Suppression of Host Defense Against Influenza A Virus

2024-01-21 | GSE183922 | GEO

Myeloid Zfhx3 Deficiency Protects Against Hypercapnia-induced Suppression of Host Defense Against Influenza A Virus

Project description:Myeloid Zfhx3 Deficiency Protects Against Hypercapnia-induced Suppression of Host Defense Against Influenza A Virus

| PRJNA762340 | ENA

mTOR pathway modulation improves hypercapnia-induced satellite cell autophagy arrest and dysfunctional myogenesis.

Project description:Chronic CO2 retention, or hypercapnia, occurs in pulmonary diseases and leads to skeletal muscle wasting. Muscle wasting and hypercapnia are independently associated with substantial mortality. While abnormal skeletal muscle stem -satellite- cells, contribute to impaired myogenesis in pulmonary diseases, no mechanistic data exists on hypercapnia-driven dysfunctional satellite cells and myogenesis in-vivo. Autophagy regulates satellite cell activation and myogenesis, and while elevated CO2 inhibits autophagy in inflammatory cells, it has never been evaluated in the context of hypercapnia-driven abnormal myogenesis. Using lineage tracing in pre- and post-stem cell transplantation experiments, we show that hypercapnia undermines both Pax7- and α-7 integrin-expressing satellite cells activation, replication and myogenesis. Satellite cells’ multi-omic analyses indicate that hypercapnia disrupts multiple pathways regulated by autophagy. Moreover, autophagy-specific LC3 fluorescence-reporting mouse and cellular data demonstrate that hypercapnia reduces expressions of AMPK and Ulk1, which critically participate in autophagosome formation, and has no effect on the antagonistic mTOR pathway including Ulk1 serine-757 phosphorylation. Moreover, Atg7 knockout-driven loss of autophagy function phenocopies the effects on hypercapnia. After rapamycin administration, the hypercapnia-induced myogenic deficit is corrected by a sharp AMPK activation leading to the autophagy-stimulatory Ulk1 phosphorylation at serine-555, autophagy acceleration, increased satellite cells replication and improved myogenesis post-satellite cells transplantation.

2025-01-15 | GSE266996 | GEO

Hypercapnia Alters Expression of Immune Response, Nucleosome Assembly and Lipid Metabolism Genes in Differentiated Human Bronchial Epithelial Cells

Project description:Hypercapnia, the elevation of CO2 in blood and tissues, commonly occurs in severe acute and chronic respiratory diseases, and is associated with increased risk of mortality. Recent studies have shown that hypercapnia adversely affects innate immunity, host defense, lung edema clearance, and cell proliferation. Airway epithelial dysfunction is a feature of advanced lung disease, but the effect of hypercapnia on airway epithelium is unknown. Thus, in the current study we examined the effect of normoxic hypercapnia (20% CO2 for 24 h) vs normocapnia (5% CO2), on global gene expression in differentiated normal human airway epithelial cells. Gene expression was assessed on Affymetrix microarrays, and subjected to gene ontology analysis for biological process and cluster-network representation. We found that hypercapnia downregulated the expression of 183 genes and upregulated 126. Among these, major gene clusters linked to immune responses and nucleosome assembly were largely downregulated, while lipid metabolism genes were largely upregulated. The overwhelming majority of these genes were not previously known to be regulated by CO2. These changes in gene expression indicate the potential for hypercapnia to impact bronchial epithelial cell function in ways that may contribute to poor clinical outcomes in patients with severe acute or advanced chronic lung diseases.

2018-09-11 | GSE110362 | GEO

ZFHX3 acts as a tumor suppressor in prostate cancer by targeting FTO-mediated m6A demethylation

Project description:Zinc-finger homeobox 3 (ZFHX3, also known as ATBF1) suppresses prostatic tumorigenesis. ZFHX3 is frequently found to have numerous deletions in human prostate cancer (PCa). However, the underlying molecular function of ZFHX3 during prostatic tumorigenesis is not well understood. N6-methyladenosine (m6A) modification in RNA plays a critical role in the development of cancers; however, the relationship between ZFHX3 and m6A modification is largely unknown in PCa. In this study, we found that ZFHX3 knockdown decreased total m6A levels through enhancing the transcriptional activity of FTO in PCa cells. Importantly, FTO inhibition suppressed cell proliferation and rescued the promoting function of ZFHX3 knockdown on cell proliferation. In vivo, we verified that FTO was upregulated and ZFHX3 was decreased in PCa patients and that a high level of ZFHX3 is indispensable for low FTO expression and is correlated with better patient survival. Through transcriptome sequencing and Me-RIP sequencing, we revealed that E2F2 and CDKN2C were the direct targets of FTO-mediated m6A modification and ZFXH3 was required for the regulation of FTO on E2F2 and CDKN2C expression. Unexpectedly, we uncovered that ZFHX3 expression was in return regulated by FTO in a m6A-dependent way. These findings establish a novel crosstalk mechanism between ZFHX3 and FTO in prostatic tumorigenesis.

2023-10-31 | GSE244356 | GEO

Loss of the Atrial Fibrillation-related gene, Zfhx3, Results in Atrial Dilation and Arrhythmias by Disruption of Genes Essential for Cardiovascular Homeostasis

Project description:Background: ZFHX3, a gene that encodes a large transcription factor, is the second-most significantly associated locus with AF, but its function in the heart is unknown. This study aims to identify causative genetic variation related to AF at the ZFHX3 locus and examine the impact of Zfhx3 loss on cardiac function in mice. Methods: CRISPR-Cas9 genome editing, chromatin immunoprecipitation, and luciferase assays in pluripotent stem cell-derived cardiomyocytes were used to identify causative genetic variation related to AF at the ZFHX3 locus. Cardiac function was assessed by echocardiography, MRI, electrophysiology studies, calcium imaging, and RNA sequencing in mice with heterozygous and homozygous cardiomyocyte-restricted Zfhx3 deletion (Zfhx3 Het and KO, respectively). Human cardiac single-nucleus ATAC-sequencing data was analyzed to determine which genes in atrial cardiomyocytes are directly regulated by ZFHX3. Results: We found SNP rs12931021 modulates an enhancer regulating ZFHX3 expression, and the AF risk allele is associated with decreased ZFHX3 transcription. We observed a gene-dose response in AF susceptibility withZfhx3KO mice having higher incidence, frequency, and burden of AF thanZfhx3Het and WT mice, with alterations in conduction velocity, atrial action potential duration, calcium handling and the development of atrial enlargement and thrombus, and dilated cardiomyopathy. Zfhx3 loss results in atrial-specific differential effects on genes and signaling pathways involved in cardiac pathophysiology and AF. Conclusions: Our findings implicate ZFHX3 as the causative gene at the 16q22 locus for AF, and cardiac abnormalities caused by loss of cardiac Zfhx3 are due to atrial-specific dysregulation of pathways involved in AF-susceptibility. Together, these data reveal a novel and important role for Zfhx3 in the control of cardiac genes and signaling pathways essential for normal atrial function.

2023-06-30 | GSE229525 | GEO

Buffered hypercapnia alters the transcriptional profile in monocytes.

Project description:In monocytes we used RNA-sequencing to investigate the effect of 4hrs of exposure to buffered hypercapnia (10% CO2) compared to normocapnia (5% CO2) with and without the pro-inflammatory stimulus LPS (2.5ug/ml) for the final 2hrs. Buffered hypercapnia causes transcriptional changes associated with altered metabolic function in both the basal and stimulated states.

2023-04-07 | GSE206333 | GEO

Drosophila elevated CO2 (hypercapnia) microarray

Project description:The effects of elevated CO2 (hypercapnia) on organisms are not well known, nor are the molecular pathways by which organisms sense CO2. We have performed microarray analysis on Drosophila in order to develop a genetic model for better understanding the effects of CO2. Equal numbers of 5-day old male and female flies (at least 40 total) were exposed to 13% CO2 or air for 24h and RNA extracted. Gene expression changes in CO2 compared with air were analyzed. Experiments were performed in triplicate and the 3 separate microarray experiments are included.

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Drosophila elevated CO2 (hypercapnia) microarray

2009-09-30 | GSE17444 | GEO