IL-32: A Host Proinflammatory Factor against Influenza Viral Replication Is Upregulated by Aberrant Epigenetic Modifications during Influenza A Virus Infection

Li, Wei; Sun, Wei; Liu, Li; Yang, Fang; Li, Yongkui; Fang, Jianjun; Zhang, Wenjing; Wu, Jianguo; Zhu, Ying

doi:10.4049/jimmunol.0902667

Cited by 114 publications

(119 citation statements)

References 40 publications

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“…Earlier studies have revealed that promoter hypermethylation suppresses gene expression, since up-methylated CpG sites may block the combination of active transcription factors (TFs) at the binding site (Li et al, 2010;Wang et al, 2010). Using the TFSEARCH software, three active TFs (ADR1, GATA-1 and GATA-2) were predicted to be located at the CpG sites of the bovine CD4 promoter.…”

Section: Discussionmentioning

confidence: 99%

Aberrant promoter methylation of the CD4 gene in peripheral blood cells of mastitic dairy cows

Wang

Zhang

He³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. Bovine mastitis is the most common and costly disease of dairy cattle. Cluster of differentiation 4 (CD4) is closely related to the immune response in mastitis. We quantified promoter CpG methylation levels of the CD4 gene in Chinese Holsteins with clinical mastitis (CM) and in healthy controls; these levels were quantitatively detected with bisulfite pyrosequencing assays and confirmed by cloning sequencing. We found that the bovine CD4 promoter had 16% more methyl groups in the cows with CM (75.0 ± 5.8%) compared to the controls (59.0 ± 8.5%). The decreased expression level of CD4 in CM cows may be downregulated by the increased DNA methylation levels in the CD4 promoter. Two-dimensional hierarchical clustering analyses showed large differences in promoter CD4 methylation between mastitic and healthy cows; the dendrogram clearly distinguished the cows with clinical mastitis from healthy controls based on methylation levels. The DNA methylation level of the CD4 gene was strongly influenced by mastitis status in all comparisons. We suggest that 6229 ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 12 (4): 6228-6239 (2013) DNA methylation changes at the CD4 promoter in mastitic cows the DNA methylation level of the CD4 promoter can be used as a molecular marker for clinical mastitis in dairy cows.

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Section: Discussionmentioning

confidence: 99%

Aberrant promoter methylation of the CD4 gene in peripheral blood cells of mastitic dairy cows

Wang

Zhang

He³

et al. 2013

Genet. Mol. Res.

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“…DNA methylation analysis. Previous studies of CpGs in the promoter regions of the interleukin-6 gene (IL-6) and IL-32 suggest that these can be demethylated due to inhibition of Dnmts during influenza A virus infection (31,32). We therefore investigated if the relative levels of transcripts encoding three different enzymes (Dnmt1, Dnmt3a, or Dnmt3b) and transcripts encoding ERVWE1, IL-6, or IL-32 were altered in response to influenza A/WSN/33 virus infection in a neuronal epithelioma cell line (SK-N-MC), a lung carcinoma cell line (A549), a kidney epithelioma cell line (293A), or primary fibroblasts.…”

Section: Regulation Of Herv-w Transcription By Influenza A/wsn/33 Virmentioning

confidence: 99%

“…An increasing body of literature suggests that viral infections can modify the methylation status of host DNA in cells of rat and human origin (27)(28)(29)(30). Recent publications suggest that influenza A virus can cause CpG demethylation by interfering with DNA methyltransferase (Dnmt) activity (31,32). In addition, a DNA methylation-independent pathway has been reported in the proviral silencing of endogenous retroviruses (ERVs) in mouse embryonic stem cells (mESCs) through trimethylation of H3K9 (33).…”

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confidence: 99%

Transcriptional Derepression of the ERVWE1 Locus following Influenza A Virus Infection

Nellåker

Sabunciyan

et al. 2014

J Virol

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Syncytin-1, a fusogenic protein encoded by a human endogenous retrovirus of the W family (HERV-W) element (ERVWE1), is expressed in the syncytiotrophoblast layer of the placenta. This locus is transcriptionally repressed in adult tissues through promoter CpG methylation and suppressive histone modifications. Whereas syncytin-1 appears to be crucial for the development and functioning of the human placenta, its ectopic expression has been associated with pathological conditions, such as multiple sclerosis and schizophrenia. We previously reported on the transactivation of HERV-W elements, including ERVWE1, during influenza A/WSN/33 virus infection in a range of human cell lines. Here we report the results of quantitative PCR analyses of transcripts encoding syncytin-1 in both cell lines and primary fibroblast cells. We observed that spliced ERVWE1 transcripts and those encoding the transcription factor glial cells missing 1 (GCM1), acting as an enhancer element upstream of ERVWE1, are prominently upregulated in response to influenza A/WSN/33 virus infection in nonplacental cells. Knockdown of GCM1 by small interfering RNA followed by infection suppressed the transactivation of ERVWE1. While the infection had no influence on CpG methylation in the ERVWE1 promoter, chromatin immunoprecipitation assays detected decreased H3K9 trimethylation (H3K9me3) and histone methyltransferase SETDB1 levels along with influenza virus proteins associated with ERVWE1 and other HERV-W loci in infected CCF-STTG1 cells. The present findings suggest that an exogenous influenza virus infection can transactivate ERVWE1 by increasing transcription of GCM1 and reducing H3K9me3 in this region and in other regions harboring HERV-W elements. IMPORTANCESyncytin-1, a protein encoded by the env gene in the HERV-W locus ERVWE1, appears to be crucial for the development and functioning of the human placenta and is transcriptionally repressed in nonplacental tissues. Nevertheless, its ectopic expression has been associated with pathological conditions, such as multiple sclerosis and schizophrenia. In the present paper, we report findings suggesting that an exogenous influenza A virus infection can transactivate ERVWE1 by increasing the transcription of GCM1 and reducing the repressive histone mark H3K9me3 in this region and in other regions harboring HERV-W elements. These observations have implications of potential relevance for viral pathogenesis and for conditions associated with the aberrant transcription of HERV-W loci.

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“…This synergistic effect may result from removal of the inhibitory effect of promoter methylation coupled with transcriptional activation by transcription factors, like influenza virus. 32,36 Since our results did not reveal changes in MIR23A-5p promotor CpG methylation, expression of this miRNA may be regulated by other mechanisms, rather than epigenetic alteration in response to B. pseudomallei infection. Taken together, we concluded that the increased expression of MIR4458, MIR4667-5p, and MIR4668-5p observed in A549 cells was attributed to specific alteration in methylation of promoter CpG islands caused by B. pseudomallei infection.…”

Section: Discussionmentioning

confidence: 86%

“…31 Influenza virus specifically regulates the expression of IL6 and IL32 by promoter demethylation. [32][33] Helicobacter pylori has also been found to regulate PTGS2 gene activation by dynamic changes of CpGs methylation at the PTGS2 promoter. 34 In addition, H. pylori-associated DNA methylation alteration occurs to CpG islands of miRNA genes, which leads to change in expression of a subset of host miRNAs.…”

Section: Discussionmentioning

confidence: 99%

Burkholderia pseudomallei survival in lung epithelial cells benefits from miRNA-mediated suppression of ATG10

Yao

Zhu

et al. 2015

Autophagy

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(2015) Burkholderiapseudomallei survival in lung epithelial cells benefits from miRNA-mediated suppression of ATG10, Autophagy, 11:8, 1293-1307, DOI: 10.1080/15548627.2015 Keywords: ATG10, autophagy, Burkholderia pseudomallei, DNA methylation, MIR4458, MIR4667-5p, MIR4668-5pAbbreviations: 3-MA, 3-methyladenine; 3 0 UTR, 3 0 -untranslated region; 5-Aza-CdR, 5-aza-2 0 -deoxycytidine; ACTB, actin, b; ATG4C, autophagy-related 4C, cysteine peptidase; ATG5, autophagy-related 5; ATG10, autophagy-related 10; ATG12, autophagyrelated 12; B. pseudomallei, Burkholderia pseudomallei; CFU, colony forming unit; CQ, chloroquine; DNMT1, DNA (cytosine-5-)-methyltransferase 1; DRAM2, DNA-damage regulated autophagy modulator 2; MAP1LC3B, microtubule-associated protein 1 light chain 3 b; miRNAs, microRNAs; MOI, multiplicity of infection; MSP, methylation-specific PCR; PBS, phosphate-buffered saline; p.i., postinfection; Rapa, rapamycin; siRNA, small interfering RNA; SQSTM1, sequestosome 1; TEM, transmission electron microscopy.Burkholderia pseudomallei is the causative agent of melioidosis, a disease with high mortality, which is prevalent in tropical regions of the world. A recent study shows that B. pseudomallei can survive inside mammalian cells because of its ability to actively evade cell autophagy. However, the underlying mechanisms remain unclear. In the present study, based on microarray screening, we found that ATG10 was downregulated following B. pseudomallei infection in A549 human lung epithelial cells. Forced expression of ATG10 accelerated the elimination of intracellular B. pseudomallei by enhancing the process of autophagy. Moreover, MIR4458, MIR4667-5p, and MIR4668-5p were found, by microarray screening, to be upregulated in response to B. pseudomallei infection. These 3 novel miRNAs, MIR4458, MIR4667-5p, and MIR4668-5p, targeted to the 3 0 -untranslated region of ATG10 in different time-course and spatial manners. Upregulation of these miRNAs reduced the level of ATG10 and inhibited autophagy, leading to increasing survival rate of intracellular B. pseudomallei. Furthermore, the increase of these miRNAs was correlated with the reduced promoter methylation status in A549 cells in response to B. pseudomallei infection. Our results reveal that 3 novel miRNAs regulate autophagymediated elimination of B. pseudomallei by targeting ATG10, and provide potential targets for clinical treatment.

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IL-32: A Host Proinflammatory Factor against Influenza Viral Replication Is Upregulated by Aberrant Epigenetic Modifications during Influenza A Virus Infection

Abstract: Material Supplementary 7.DC1http://www.jimmunol.org/content/suppl/2010/10/01/jimmunol.090266References

Cited by 114 publications

References 40 publications

Aberrant promoter methylation of the CD4 gene in peripheral blood cells of mastitic dairy cows

Aberrant promoter methylation of the CD4 gene in peripheral blood cells of mastitic dairy cows

Transcriptional Derepression of the ERVWE1 Locus following Influenza A Virus Infection

Burkholderia pseudomallei survival in lung epithelial cells benefits from miRNA-mediated suppression of ATG10

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