Hypoxia regulates endogenous double-stranded RNA production via reduced mitochondrial DNA transcription
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE153557 | GEO | 2021/06/30
REPOSITORIES: GEO
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Project description:We precipitated dsRNA using the monoclonal J2 antibody and deep-sequenced the enriched samples from testis of juvenile dicer knock-out mice, age matched controls and adult animals. The dsRNA transcriptome is significantly less complex in juvenile mice as compared to adult controls and, possibly as a consequence, the knock-out of Dicer had only a minor effect of the total number of transcribed regions associated with dsRNA. The genes that potentially generate dsRNA are significantly expressed in isolated sperm cells with particular enrichment in pachytene spermatocytes.
2021-06-01 | GSE149814 | GEO
Project description:Hypoxia is a hallmark of renal ischemia reperfusion injury (IRI) and serves as an essential regulator of innate immune responses during this process, although the mechanisms of this regulation remain unclear. Here, we show that dendritic cell (DC)-specific genetic ablation of hypoxia-inducible factor (HIF) 2α, a transcription factor induced by oxygen shortage, leads to hyperactivation of natural killer T cells (NKTs), ultimately exacerbating renal IRI in mice. HIF-2α deficiency in DCs triggers IFN-γ and IL-4 production in NKTs, along with upregulation of type I interferon (IFN) and chemokine responses critical for NKT activation. Mechanistically, loss of HIF-2α in DCs promotes their expression of CD36, a scavenger receptor for lipid uptake, resulting in increased lipid accumulation. Furthermore, HIF-2α binds directly to a reverse hypoxia-responsive element (rHRE) in the CD36 promoter, supporting its transcriptional regulation of CD36. Importantly, CD36 blockade by sulfo-N-succinimidyl oleate (SSO), reduces NKT activation and abolishes the exacerbation of renal IRI in mice with DC-specific HIF-2α knockout. Taken together, our study reveals a previously unrecognized role of a HIF-2α-CD36 regulatory axis in rewiring DC lipid metabolism under IRI-associated hypoxia, and suggests a potential therapeutic target to resolve long-standing obstacles in clinical treatment of this severe complication.
2022-09-23 | GSE199875 | GEO
Project description:Hypoxia inducible factor 1 (HIF1) has been shown to cooperate with the androgen receptor (AR) in activation of oncogenic pathways in prostate cancer (PCa). Here we hypothesized that HIF1 also plays a role in PCa response to androgen deprivation therapy (ADT). Comparison of gene expression profiles of androgen exposed (AE) and androgen deprived (AD) CWR22 PCa xenografts identified 596 upregulated and 748 downregulated genes after ADT. Gene ontology (GO) analysis of the differentially expressed genes showed significant enrichment of the biological processes cell proliferation, cell cycle and metabolism and suggested suppression of these processes after ADT. A set of 80 hypoxia-inducible genes were identified in 22Rv1 and LNCaP cell lines treated with hypoxia and showed considerable overlap (53%) with the downregulated genes. Immunostaining of the hypoxia marker pimonidazole showed no difference between AE- and AD-tumors. Comparison of the differentially expressed genes with lists of 1115 direct AR- and 276 direct HIF1-target genes identified 138 AR- and 40 HIF1-targets that were regulated after ADT, including six shared AR- and HIF1-targets for which downregulation was confirmed with RT-PCR. Most HIF1-targets were downregulated and included in the significant biological processes and the set of hypoxia-inducible genes. The downregulation of HIF1-targets was consistent with decreased HIF1A immunostaining in AD- compared to AE-tumors (p=0.002). A decrease in HIF1A immunostaining after ADT was also demonstrated in a cohort of 35 PCa patients (p<0.001). These data suggest suppressed HIF1-signaling after ADT and a shared role of HIF1 and AR in the regressive phase of PCa after ADT. Prostate cancer xenografts were subjected to adrogen deprivation therapy and analysed with regard to changes in gene expressions. Cell culture experiments were performed to generate prostate cancer specific gene lists associated with hypoxia.
2013-10-02 | E-GEOD-42868 | biostudies-arrayexpress
Project description:In vertebrates, the presence of viral RNA in the cytosol is sensed by members of the RIG-I like receptor (RLR) family , which signal to induce production of type I interferons (IFN). These key anti-viral cytokines act in a paracrine and autocrine manner to induce hundreds of interferon-stimulated genes (ISGs), whose protein products restrict viral entry, replication and budding. ISGs include the RLRs themselves: RIG-I, MDA5 and the least-studied family member, LGP2. In contrast, the IFN system is absent in plants and invertebrates, which defend themselves from viral intruders using RNA interference (RNAi). In RNAi, the endoribonuclease Dicer cleaves virus-derived double stranded RNA (dsRNA) into small interfering RNAs (siRNAs) that target complementary viral RNA for cleavage. Interestingly, the RNAi machinery is conserved in mammals and we have recently demonstrated that it is able to participate in mammalian antiviral defence in conditions in which the IFN system is suppressed. In contrast, when the IFN system is active, one or more ISGs act to mask or suppress antiviral RNAi. Here, we demonstrate that LGP2 constitutes one of the ISGs that can inhibit antiviral RNAi in mammals. We identify Dicer as an LGP2-associated protein and show that LGP2 inhibits Dicer cleavage of dsRNA into siRNAs both in vitro and in vivo. Further, we show that in cells lacking an IFN response, ectopic expression of LGP2 interferes with RNAi-dependent suppression of gene expression. Thus, the inefficiency of RNAi as a mechanism of antiviral defence in mammalian somatic cells can be in part attributed to Dicer inhibition by LGP2 induced by type I IFNs.
2018-01-17 | PXD008364 | Pride
Project description:To investigate the detailed molecular mechanisms for the regulatory role of HIF-2α in experimental colitis, microarray gene expression analysis was performed on colon RNA isolated from 6- to 8-week-old Hif-2αF/F, Hif-2αlΔIE mice treated with 3%DSS for 3 days. Background & Aims: Hypoxic inflammation is characterized by decreased oxygen tension in inflammatory foci, and is a notable feature in inflammatory bowel disease (IBD). Hypoxic response is mediated by transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α, both of which are highly induced in IBD. HIF-1α is a protective factor that limits intestinal barrier dysfunction during inflammation. However, the role of HIF-2α has not been assessed in hypoxic inflammation and IBD. Methods: A hypoxia reporter mouse model was used to test the presence of hypoxia and HIF-2α in dextran sulfate sodium (DSS) and Citrobacter rodentium (C.rod)-induced colitis. The role of HIF-2α in these mouse models of colitis was further assessed in mice with an intestinal epithelium-specific gain- and loss-of-function of HIF-2α. Results: Induction of hypoxia and HIF-2α was confirmed in both murine experimental colitis models and human IBD samples. Disruption of HIF-2α attenuated colonic inflammation whereas stabilization of HIF-2α potentiated inflammation in mouse models of colitis. Interestingly, intestine specific overexpression of HIF-2α but not HIF-1α leads to spontaneous colitis and premature death in mice. Further mechanistic analysis showed that HIF-2α is a driver for pro-inflammatory response and is critical regulator of intestinal epithelial-derived tumor necrosis factor (TNF)-α. Blocking TNF-α completely ameliorated HIF-2α potentiated intestinal inflammation. Conclusions: These data demonstrate that HIF-2α is a critical transcription factor essential in intestinal epithelium elicited inflammatory response. Global gene expression profiling in colon RNAs isolated from 7-week-old Hif-2αF/F (n=6, Shah 007) and Hif-2αΔIE (n=5, Shah 008).
2013-02-28 | E-GEOD-43416 | biostudies-arrayexpress
Project description:C. elegans mutants deleted for TDP-1, an ortholog of the neurodegeneration-associated RNA binding protein TDP-43, display only mild phenotypes. Nevertheless, transcriptome sequencing revealed that many RNAs were altered in accumulation and/or processing in the mutant. Analysis of these transcriptional abnormalities demonstrates that a primary function of TDP-1 is to limit formation or stability of double-stranded RNA. Specifically, we found that deletion of tdp-1: 1) preferentially alters the accumulation of RNAs with inherent double stranded structure (dsRNA); 2) increases the accumulation of nuclear dsRNA foci, 3) enhances the frequency of adenosine-to-inosine RNA editing, and 4) dramatically increases the amount of transcripts immunoprecipitable with a dsRNA-specific antibody, including intronic sequences, RNAs with antisense overlap to another transcript, and transposons. We also show that TDP-43 knockdown in human cells results in accumulation of dsRNA , indicating that suppression of dsRNA is a conserved function of TDP-43 in mammals. Altered accumulation of structured RNA may account for some of the previously described molecular phenotypes (e.g., altered splicing) resulting from reduction of TDP-43 function. 24 samples: 3 tdp-1 polyA samples with 3 N2 controls, 3 tdp1J2 immunoprecipitated samples and tdp1 total RNA input with 3 N2 J2 immunoprecipitated controls (with N2 input), 3 tdp1 total RNA samples for RNA editing analysis with 3 N2 total RNA controls and an adr-2 mutant control, 2 tdp1 CHIPseq samples with RNAsecontrol.
2014-11-19 | E-GEOD-61581 | biostudies-arrayexpress
Project description:Although viral infection is thought to be associated with subacute thyroiditis and probably with autoimmune thyroid disease, possible changes in thyroid function during the prodromal period of infection or subclinical infection remain largely unknown. Recently, it was shown that pathogen-associated molecular patterns stimulate Toll-like receptors (TLR) and activate innate immune responses by producing type I interferons (IFN). Using a human thyroid follicle culture system, in which de novo synthesized thyroid hormones are released into the culture medium under physiological concentrations of hTSH, we studied the effects of polyinosinic-polycytidylic acid (Poly(I:C)), a chemical analog of viral double-stranded RNA (dsRNA), on TSH-induced thyroid function. Thyrocytes expressed ligands for dsRNA (TLR 3, CD14, and RIG-1) comparable to the TSH receptor. DNA microarray and real-time PCR analyses revealed that dsRNA increased the expression of mRNA for TLR3, IFN-g, interferon-regulating factors, proinflammatory cytokines, and class I MHC, whereas genes associated with thyroid hormonogenesis (NIS, peroxidase, deiodinases) were suppressed. In accordance to these data, Poly(I:C) suppressed TSH-induced 125I uptake and hormone synthesis dose-dependently, accompanied by a decrease in the ratio of 125I-T3/125I-T4 released into the culture medium, whereas peptidoglycan, lipopolysaccharides, or unmethylated CpG DNA, ligands for TLR2, TLR4, and TLR9, respectively, had no significant effect. These inhibitory effects of Poly(I:C) were not blocked by a neutralizing antibody against TLR3 and an anti-IFN alpha/beta receptor antibody. These in vitro findings suggest that when thyrocytes are infected with certain viruses, dsRNA formed intracellularly in thyrocytes may be a cause for thyroid dysfunction, leading to development of autoimmune thyroiditis. This data was published in Endocrinology, vol.148, 3226-3235, 2007. Experiment Overall Design: Two conditioned experimets, control vs. double-stranded RNA (polyI-C), cultured for 6
2008-10-21 | E-GEOD-12154 | biostudies-arrayexpress
Project description:Inflammation is a significant risk factor for colon cancer. Recent work has demonstrated essential roles for several infiltrating immune populations in the metaplastic progression following inflammation. Hypoxia and stabilization of hypoxia-inducible factors (HIFs) are hallmark features of inflammation and solid tumors. Previously, we demonstrated an important role for tumor epithelial HIF-2α in colon tumors; however, the function of epithelial HIF-2α as a critical link in the progression of inflammation to cancer has not been elucidated. In colitis-associated colon cancer models, epithelial HIF-2α was essential in tumor growth. Concurrently, epithelial disruption of HIF-2α significantly decreased neutrophils in the colon tumor microenvironment. Intestinal epithelial HIF-2α-overexpressing mice demonstrated that neutrophil recruitment was a direct response to increased epithelial HIF-2α signaling. High-throughput RNA sequencing (RNA-seq) analysis of HIF-2α-overexpressing mice in conjunction with data mining from the Cancer Genome Atlas showed that the neutrophil chemokine CXCL1 gene was highly upregulated in colon tumor epithelium in a HIF-2α-dependent manner. Using selective peptide inhibitors of the CXCL1-CXCR2 signaling axis identified HIF-2α-dependent neutrophil recruitment as an essential mechanism to increase colon carcinogenesis. These studies demonstrate that HIF-2α is a novel regulator of neutrophil recruitment to colon tumors and that it is essential in shaping the protumorigenic inflammatory microenvironment in colon cancer.
2021-04-27 | GSE173363 | GEO
Project description:Loss of tumor suppressor proteins, such as the retinoblastoma protein (Rb), results in tumor progression and metastasis. Metastasis is facilitated by low oxygen availability within the tumor that is detected by hypoxia inducible factors (HIFs). The HIF1 complex, HIF1α and dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT), is the master regulator of the hypoxic response. Previously, we demonstrated that Rb represses the transcriptional response to hypoxia by virtue of its association with HIF1. In this report, we further characterized the role of Rb in HIF1-regulated genetic programs by stably ablating Rb expression with retrovirally-introduced short hairpin RNA in LNCaP and 22Rv1 human prostate cancer cells. DNA microarray analysis revealed that Rb regulates specific chromosomal gene clusters and loss of Rb in conjunction with hypoxia leads to dysregulation of HIF1-regulated genetic programs that increase cell invasion and promote neuroendocrine differentiation. For the first time, we have established a direct link between hypoxic tumor environments, Rb inactivation and progression to late stage metastatic neuroendocrine prostate cancer. Understanding the molecular pathways responsible for progression of benign prostate tumors to metastasized and lethal forms will aid in the development of more effective prostate cancer therapies. RNAs derived from human LNCaP cells stably infected with either scrambled control shRNA or a shRNA directed to RB1. Cells were exposed to either 24 h hypoxia (1% O2) or maintained under normoxic conditions. Biological triplicates were tested and compared.
2016-02-24 | E-GEOD-78245 | biostudies-arrayexpress
Project description:Dynamic N6-methyladenosine (m6A) modification was previously identified as a ubiquitous post-transcriptional regulation that affected mRNA homeostasis. However, the m6A-related epitranscriptomic alterations and functions remain elusive in human diseases such as cancer. Here we show that hypoxia regulates the ‘reader’ protein YTH domain family 2 (YTHDF2), to eventually stabilize the methylated oncogene mRNAs in inflammation-associated liver cancer. YTHDF2 silenced in human cancer cells or depleted in mouse hepatocytes evoked pro-inflammatory responses and accelerated tumor growth and metastatic progression. Under hypoxia, YTHDF2 processed the decay of m6A-containing interleukin 11 (IL11) and serpin family E member 2 (SERPINE2) mRNAs, which were responsible for the inflammation-mediated malignancy. Reciprocally, YTHDF2 transcription succumbed to hypoxia-inducible factor-2α (HIF-2α). Administration of a HIF-2α antagonist (PT2385) restored YTHDF2-programed epigenetic machinery and repressed liver cancer. Hence, our findings provide a new insight into the mechanism by which hypoxia adapts m6A-mRNA editing to promote cancer.
2020-03-17 | GSE120860 | GEO