Dataset Information

Genome-wide analysis of HIF-2? chromatin binding sites under normoxia in human bronchial epithelial cells (BEAS-2B) suggests its diverse functions.

ABSTRACT: Constitutive functional HIF-2? was recently identified in cancer and stem cell lines under normoxia. In this study, BEAS-2B, a bronchial epithelial cell line, was shown to constitutively express active HIF-2? under normoxia and exhibit markers of pluripotency including Oct-4, Nanog, and sphere formation. Oct-4 expression was reduced after knockdown of HIF-2? under normoxia. Global enrichment analysis of HIF-2? demonstrated the diverse functions of HIF-2? under normoxia. Bioinformatics analysis of the enriched loci revealed an enhancer role of HIF-2? binding sites, involvement of HIF-2? interacting proteins, and enriched de novo motifs which suggest the diverse role of HIF-2? in pseudohypoxia. The low ratio of the discovered loci overlapping with those revealed in cancer cell lines 786-O (16.1%) and MCF-7 (15.9%) under hypoxia indicated a prevailing non-canonical mechanism. Hypoxia had positive, marginal or adverse effects on the enrichment of the selected loci in ChIP-PCR assays. Deletion of the N-terminal activation domain (N-TAD) of HIF-2? disrupted the reporting activity of two of the loci annotated to ELN and ANKRD31. Hypoxia incurring abundance variation of HIF-2? may misrepresent the N-TAD functions as canonical hypoxia inducible features via C-TAD activation. Elucidation of the pseudohypoxia functions of constitutive HIF-2? is useful for resolving its role in malignancy and pluripotency.

SUBMITTER: Lee MC

PROVIDER: S-EPMC4931692 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Genome-wide analysis of HIF-2α chromatin binding sites under normoxia in human bronchial epithelial cells (BEAS-2B) suggests its diverse functions.

Lee Meng-Chang MC Huang Hsin-Ju HJ Chang Tzu-Hao TH Huang Hsieh-Chou HC Hsieh Shen-Yuan SY Chen Yi-Siou YS Chou Wei-Yuan WY Chiang Chiao-Hsi CH Lai Ching-Huang CH Shiau Chia-Yang CY

Scientific reports 20160704

Constitutive functional HIF-2α was recently identified in cancer and stem cell lines under normoxia. In this study, BEAS-2B, a bronchial epithelial cell line, was shown to constitutively express active HIF-2α under normoxia and exhibit markers of pluripotency including Oct-4, Nanog, and sphere formation. Oct-4 expression was reduced after knockdown of HIF-2α under normoxia. Global enrichment analysis of HIF-2α demonstrated the diverse functions of HIF-2α under normoxia. Bioinformatics analysis o ...[more]

PMID: 27373565

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Project description:BACKGROUND:Emissions from diesel vehicles and biomass burning are the principal sources of primary ultrafine particles (UFP). The exposure to UFP has been associated to cardiovascular and pulmonary diseases, including lung cancer. Although many aspects of the toxicology of ambient particulate matter (PM) have been unraveled, the molecular mechanisms activated in human cells by the exposure to UFP are still poorly understood. Here, we present an RNA-seq time-course experiment (five time point after single dose exposure) used to investigate the differential and temporal changes induced in the gene expression of human bronchial epithelial cells (BEAS-2B) by the exposure to UFP generated from diesel and biomass combustion. A combination of different bioinformatics tools (EdgeR, next-maSigPro and reactome FI app-Cytoscape and prioritization strategies) facilitated the analyses the temporal transcriptional pattern, functional gene set enrichment and gene networks related to cellular response to UFP particles. RESULTS:The bioinformatics analysis of transcriptional data reveals that the two different UFP induce, since the earliest time points, different transcriptional dynamics resulting in the activation of specific genes. The functional enrichment of differentially expressed genes indicates that the exposure to diesel UFP induces the activation of genes involved in TNF? signaling via NF-kB and inflammatory response, and hypoxia. Conversely, the exposure to ultrafine particles from biomass determines less distinct modifications of the gene expression profiles. Diesel UFP exposure induces the secretion of biomarkers associated to inflammation (CCXL2, EPGN, GREM1, IL1A, IL1B, IL6, IL24, EREG, VEGF) and transcription factors (as NFE2L2, MAFF, HES1, FOSL1, TGIF1) relevant for cardiovascular and lung disease. By means of network reconstruction, four genes (STAT3, HIF1a, NFKB1, KRAS) have emerged as major regulators of transcriptional response of bronchial epithelial cells exposed to diesel exhaust. CONCLUSIONS:Overall, this work highlights modifications of the transcriptional landscape in human bronchial cells exposed to UFP and sheds new lights on possible mechanisms by means of which UFP acts as a carcinogen and harmful factor for human health.

Project description:Background: In classrooms high concentrations of particulate matter PM10 were measured. It is unknown whether the hazard of indoor particles is similar to that of the better studied outdoor particles. This study therefore analyzed adverse biological effects of classroom in comparison to outdoor PM10. Methods: Samples were taken from six schools during teaching hours. Genome-wide gene expression in human bronchial BEAS-2B epithelial cells was analyzed, and regulated genes were verified by quantitative PCR. Polycyclic aromatic hydrocarbons (PAH), endotoxin, and cat allergen Fel d 1 were analyzed with standard methods. Enhancement of allergic reactivity by PM10 was confirmed with CD63 upregulation in human primary basophils. Acceleration of human blood coagulation was determined with supernatants of PM10-exposed human peripheral blood monocytes. Results: Indoor PM10 induced SERPINB2 (involved in blood coagulation) and inflammatory genes (like CXCL6, CXCL1, IL6, IL8, all p<0.001). Outdoor PM10 induced xenobiotic metabolizing enzymes (CYP1A1, CYP1B1, TIPARP, all p<0.001). The induction of inflammatory genes by indoor PM10 could be explained by endotoxin (indoor 128.5±42.2EU/mg versus outdoor 13.4±21.5EU/mg, p<0.001), the induction of CYP by outdoor PAH (indoor 8.3±4.9ng/mg versus outdoor 16.7±15.2ng/mg, p<0.01). The induction of SERPINB2 was confirmed by a more rapid human blood coagulation (p<0.05). Indoor PM10 had no effect on the allergic reactivity from human primary basophils, except in cat allergic individuals. This was explained by varying Fel d 1 concentrations in indoor PM10 (p<0.001). Conclusions: Indoor PM10, compared to outdoor PM10, was 6 times higher, had a different composition, and on an equal weight basis induced more inflammatory and allergenic reactions, and accelerated blood coagulation. Outdoor PM10 had significantly lower effects, but induced detoxifying enzymes. Therefore, preliminary interventions for the reduction of classroom PM10 seem reasonable, perhaps by intensified ventilation.

Dataset Information

Genome-wide analysis of HIF-2? chromatin binding sites under normoxia in human bronchial epithelial cells (BEAS-2B) suggests its diverse functions.

Publications

Genome-wide analysis of HIF-2α chromatin binding sites under normoxia in human bronchial epithelial cells (BEAS-2B) suggests its diverse functions.

Similar Datasets

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