The aryl hydrocarbon receptor controls cyclin O to promote epithelial multiciliogenesis

Villa, Matteo; Crotta, Stefania; Dingwell, Kevin S.; Hirst, Elizabeth; Gialitakis, Manolis; Ahlfors, Helena; Smith, James C.; Stockinger, Brigitta; Wack, Andreas

doi:10.1038/ncomms12652

Cited by 22 publications

(20 citation statements)

References 53 publications

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“…Interestingly, Irf7 −/− and Ifnar2 −/− (deficient for type I IFN receptor) mice displayed normal dendritic cell development and allergic airway sensitization in response to HDM 81 , suggesting independence between type I IFN signaling and HDM-induced airway allergy when Tet1 is present. On the other hand, the AhR pathway, the second most significantly enriched pathway in our analysis, regulates airway epithelial multiciliogenesis 93 and oxidative stress responses 60 , and contributes to asthma development and exacerbation 46,62,94 . Specifically, AhR ligands attenuate allergic airway inflammation in OVA-challenged animal models 94,95 , suggesting that down-regulation of the AhR pathway by Tet1 would increase the severity of HDM-induced allergic airway inflammation.…”

Section: Discussionmentioning

confidence: 98%

TET1 contributes to allergic airway inflammation and regulates interferon and aryl hydrocarbon receptor signaling pathways in bronchial epithelial cells

Burleson

Siniard

Yadagiri

et al. 2019

Sci Rep

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Previous studies have suggested a role for Tet1 in the pathogenesis of childhood asthma. However, how Tet1 contributes to asthma remains unknown. Here we used mice deficient for Tet1 in a well-established model of allergic airway inflammation and demonstrated that loss of Tet1 increased disease severity including airway hyperresponsiveness and lung eosinophilia. Increased expression of Muc5ac , Il1 3 , Il33 , Il 1 7a , Egfr , and Tff 2 were observed in HDM-challenged Tet1-deficient mice compared to Tet1 +/+ littermates. Further, transcriptomic analysis of lung RNA followed by pathway and protein network analysis showed that the IFN signaling pathway was significantly upregulated and the aryl hydrocarbon receptor (AhR) pathway was significantly downregulated in HDM-challenged Tet1 −/− mice. This transcriptional regulation of the IFN and AhR pathways by Tet1 was also present in human bronchial epithelial cells at base line and following HDM challenges. Genes in these pathways were further associated with changes in DNA methylation, predicted binding of transcriptional factors with relevant functions in their promoters, and the presence of histone marks generated by histone enzymes that are known to interact with Tet1. Collectively, our data suggest that Tet1 inhibits HDM-induced allergic airway inflammation by direct regulation of the IFN and AhR pathways.

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Section: Discussionmentioning

confidence: 98%

TET1 contributes to allergic airway inflammation and regulates interferon and aryl hydrocarbon receptor signaling pathways in bronchial epithelial cells

Burleson

Siniard

Yadagiri

et al. 2019

Sci Rep

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“…Previous studies mainly demonstrated various mutations and important functions in respiratory disease. 13 , 22 , 23 However, studies concerning the role of CCNO in cancer are rarely reported. Therefore, the clinical significance and functional role of CCNO in human cancer, including GC, remains largely unexplored.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of CCNO decreases the tumorigenicity of gastric cancer by inducing apoptosis

Li¹,

Cao²,

Zhou³

et al. 2018

OTT

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PurposeRecently, Cyclin O (CCNO) has been reported to be a novel protein of the cyclin family. However, the clinical significance and functional roles of CCNO in human cancer, including gastric cancer (GC), remain largely unexplored. In this study, we investigated the clinical and functional roles of CCNO in GC.MethodsWe analyzed CCNO expression patterns in GC patients. To investigate the role of CCNO in malignancy of GC, we used lentivirus-delivered short hairpin RNA to knockdown CCNO expression in GC cell lines. Then multiparametric high-content screening and MTT incorporation assay were used to assess the cell proliferation capability. Cell apoptosis was detected by flow cytometry and Caspase 3/7 assays. Furthermore, the effect of CCNO on tumorigenicity of GC was also determined in vivo. Finally, microarray analysis was performed to elucidate the molecular mechanisms by which shCCNO inhibited the malignancy of GC cells.ResultsThe analysis from The Cancer Genome Atlas database revealed elevated CCNO mRNA expression in GC tissue than in the adjacent normal tissue. Immunohistochemical studies also showed that stronger cytoplasmic staining of CCNO was detected in GC tissues. Downregulation of CCNO in GC cells efficiently, through infection with the lentivirus-mediated specific short hairpin RNA, could significantly induce cell apoptosis and inhibit the proliferative properties both in vitro and in vivo. Microarray analysis further revealed 652 upregulated genes and 527 downregulated genes in the shCCNO group compared with control, and indicated that CCNO knockdown could inhibit the malignancy of GC cells through inducing genome-wide gene expression changes.ConclusionOur work is the first to reveal that elevated CCNO expression is closely associated with human GC development and that CCNO knockdown could efficiently inhibit the malignant properties of GC cells by inducing cell apoptosis. Therefore, CCNO could be used as a potential biomarker for prognosis or even as a therapeutic target in human GC.

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“…Polyaromatic hydrocarbon levels are increased in the plasma of asthmatic children and linked to a number of asthma markers 98 . The aryl hydrocarbon receptor (AhR), which plays a key role in detoxification of environmental pollutants, also regulates multiciliogenesis 99 . Importantly, although air exposure triggers AhR targeting of genes important for multiciliogenesis, toxic AhR ligands induce detoxifying cytochromes, with no overlap in target gene induction.…”

Section: Dysregulation Of the Epithelial Barrier In Asthmatic Patientsmentioning

confidence: 99%

Phenotypic and genetic aspects of epithelial barrier function in asthmatic patients

Loxham

Davies

2017

Journal of Allergy and Clinical Immunology

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The bronchial epithelium is continuously exposed to a multitude of noxious challenges in inhaled air. Cellular contact with most damaging agents is reduced by the action of the mucociliary apparatus and by formation of a physical barrier that controls passage of ions and macromolecules. In conjunction with these defensive barrier functions, immunomodulatory cross-talk between the bronchial epithelium and tissue-resident immune cells controls the tissue microenvironment and barrier homeostasis. This is achieved by expression of an array of sensors that detect a wide variety of viral, bacterial, and nonmicrobial (toxins and irritants) agents, resulting in production of many different soluble and cell-surface molecules that signal to cells of the immune system. The ability of the bronchial epithelium to control the balance of inhibitory and activating signals is essential for orchestrating appropriate inflammatory and immune responses and for temporally modulating these responses to limit tissue injury and control the resolution of inflammation during tissue repair. In asthmatic patients abnormalities in many aspects of epithelial barrier function have been identified. We postulate that such abnormalities play a causal role in immune dysregulation in the airways by translating gene-environment interactions that underpin disease pathogenesis and exacerbation.

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The aryl hydrocarbon receptor controls cyclin O to promote epithelial multiciliogenesis

Cited by 22 publications

References 53 publications

TET1 contributes to allergic airway inflammation and regulates interferon and aryl hydrocarbon receptor signaling pathways in bronchial epithelial cells

TET1 contributes to allergic airway inflammation and regulates interferon and aryl hydrocarbon receptor signaling pathways in bronchial epithelial cells

Knockdown of CCNO decreases the tumorigenicity of gastric cancer by inducing apoptosis

Phenotypic and genetic aspects of epithelial barrier function in asthmatic patients

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