Enhancer Control of MicroRNA miR-155 Expression in Epstein-Barr Virus-Infected B Cells

Wood, C. David; Carvell, Thomas; Gunnell, Andrea; Ojeniyi, Opeoluwa O.; Osborne, Cameron S.; West, Michelle J.

doi:10.1128/jvi.00716-18

Cited by 44 publications

(33 citation statements)

References 51 publications

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“…While we cannot formally exclude the possibility of off-target effects of these small molecule inhibitors, the PI3K kinase pathway has previously been indirectly implicated in regulation of miR-155 by LMP1. Notably, both Src and PI3K are required for activation of IRF4 by LMP1 (Wang et al, 2016), and IRF4 is required to regulate expression of the primary transcript of miR-155, miR-155HG or BIC, in EBV-transformed cells (Wang et al, 2011;Wood et al, 2018). Finally, LMP1 is one of four EBV genes, including LMP2a, EBNA2, and EBNA3C, which have been demonstrated to regulate miR-155 expression (Gatto et al, 2008;Lu et al, 2008;Rahadiani et al, 2008;Yin et al, 2008Yin et al, , 2016Du et al, 2011;Wang et al, 2011;Wood et al, 2018).…”

Section: A B C Dmentioning

confidence: 99%

“…Notably, both Src and PI3K are required for activation of IRF4 by LMP1 (Wang et al, 2016), and IRF4 is required to regulate expression of the primary transcript of miR-155, miR-155HG or BIC, in EBV-transformed cells (Wang et al, 2011;Wood et al, 2018). Finally, LMP1 is one of four EBV genes, including LMP2a, EBNA2, and EBNA3C, which have been demonstrated to regulate miR-155 expression (Gatto et al, 2008;Lu et al, 2008;Rahadiani et al, 2008;Yin et al, 2008Yin et al, , 2016Du et al, 2011;Wang et al, 2011;Wood et al, 2018). Collectively, our data and that of Wang et al suggest additions to the model proposed by Wood et al, where EBNA2A directly regulates miR-155HG expression and indirectly regulates miR-155HG expression through the upregulation of both LMP1 and IRF4 (Wood et al, 2018).…”

Section: A B C Dmentioning

confidence: 99%

“…Finally, LMP1 is one of four EBV genes, including LMP2a, EBNA2, and EBNA3C, which have been demonstrated to regulate miR-155 expression (Gatto et al, 2008;Lu et al, 2008;Rahadiani et al, 2008;Yin et al, 2008Yin et al, , 2016Du et al, 2011;Wang et al, 2011;Wood et al, 2018). Collectively, our data and that of Wang et al suggest additions to the model proposed by Wood et al, where EBNA2A directly regulates miR-155HG expression and indirectly regulates miR-155HG expression through the upregulation of both LMP1 and IRF4 (Wood et al, 2018). In this updated model, LMP1 can then activate or support miR-155 expression in the following ways: by PI3K p110α activation of IRF4 (Wang et al, 2011;Wood et al, 2018), by NF-κB activation (Gatto et al, 2008;Rahadiani et al, 2008;Yin et al, 2016), by p38 activation (Rahadiani et al, 2008), and by AP-1 activation (Gatto et al, 2008;Rahadiani et al, 2008;Yin et al, 2008Yin et al, , 2016.…”

Section: A B C Dmentioning

confidence: 99%

“…Four EBV genes can regulate miR-155 expression -the latent membrane proteins 1 and 2a (LMP1 and LMP2a) and the EBV nuclear antigens 2 and 3C (EBNA2 and EBNA3C; Gatto et al, 2008;Lu et al, 2008;Rahadiani et al, 2008;Yin et al, 2008Yin et al, , 2016Du et al, 2011;Wang et al, 2011;Wood et al, 2018). These EBV latent genes co-operatively regulate miR-155 expression by activating host cell signaling pathways and transcription factors, such as NF-κB (Gatto et al, 2008;Rahadiani et al, 2008;Yin et al, 2016), p38 (Rahadiani et al, 2008), IRF4 (Wang et al, 2011;Wood et al, 2018), and AP-1 (Gatto et al, 2008;Rahadiani et al, 2008;Yin et al, 2008Yin et al, , 2016, by activating expression of other latent EBV genes (Wood et al, 2018) or by directly interacting with the regulatory regions of the miR-155 host gene (miR-155HG; Wood et al, 2018). For example, EBNA2 regulates expression of miR-155HG both directly, by binding an enhancer region upstream of the miR-155HG locus, and indirectly, by upregulating the expression of LMP1 and the transcription factor IRF4 (Wood et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…These EBV latent genes co-operatively regulate miR-155 expression by activating host cell signaling pathways and transcription factors, such as NF-κB (Gatto et al, 2008;Rahadiani et al, 2008;Yin et al, 2016), p38 (Rahadiani et al, 2008), IRF4 (Wang et al, 2011;Wood et al, 2018), and AP-1 (Gatto et al, 2008;Rahadiani et al, 2008;Yin et al, 2008Yin et al, , 2016, by activating expression of other latent EBV genes (Wood et al, 2018) or by directly interacting with the regulatory regions of the miR-155 host gene (miR-155HG; Wood et al, 2018). For example, EBNA2 regulates expression of miR-155HG both directly, by binding an enhancer region upstream of the miR-155HG locus, and indirectly, by upregulating the expression of LMP1 and the transcription factor IRF4 (Wood et al, 2018). Upregulation of miR-155 by LMP1 can be blocked by small molecule inhibition of p38 and NF-κB and also requires NF-κB and AP-1 binding sites in the miR-155HG promoter (Gatto et al, 2008;Rahadiani et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Epstein-Barr Virus Latent Membrane Protein 1 Regulates Host B Cell MicroRNA-155 and Its Target FOXO3a via PI3K p110α Activation

et al. 2019

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Epstein-Barr Virus (EBV) is associated with potentially fatal lymphoproliferations such as post-transplant lymphoproliferative disorder (PTLD), a serious complication of transplantation. The viral mechanisms underlying the development and maintenance of EBV+ B cell lymphomas remain elusive but represent attractive therapeutic targets. EBV modulates the expression of host microRNAs (miRs), non-coding RNAs that regulate gene expression, to promote survival of EBV+ B cell lymphomas. Here, we examined how the primary oncogene of EBV, latent membrane protein 1 (LMP1), regulates host miRs using an established model of inducible LMP1 signaling. LMP1 derived from the B95.8 lab strain or PTLD induced expression of the oncogene miR-155. However, PTLD variant LMP1 lost the ability to upregulate the tumor suppressor miR-193. Small molecule inhibitors (SMI) of p38 MAPK, NF-κB, and PI3K p110α inhibited upregulation of miR-155 by B95.8 LMP1; no individual SMI significantly reduced upregulation of miR-155 by PTLD variant LMP1. miR-155 was significantly elevated in EBV+ B cell lymphoma cell lines and associated exosomes and inversely correlated with expression of the miR-155 target FOXO3a in cell lines. Finally, LMP1 reduced expression of FOXO3a, which was rescued by a PI3K p110α SMI. Our data indicate that tumor variant LMP1 differentially regulates host B cell miR expression, suggesting viral genotype as an important consideration for the treatment of EBV+ B cell lymphomas. Notably, we demonstrate a novel mechanism in which LMP1 supports the regulation of miR-155 and its target FOXO3a in B cells through activation of PI3K p110α. This mechanism expands on the previously established mechanisms by which LMP1 regulates miR-155 and FOXO3a and may represent both rational therapeutic targets and biomarkers for EBV+ B cell lymphomas.

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Section: A B C Dmentioning

confidence: 99%

Section: A B C Dmentioning

confidence: 99%

Section: A B C Dmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Epstein-Barr Virus Latent Membrane Protein 1 Regulates Host B Cell MicroRNA-155 and Its Target FOXO3a via PI3K p110α Activation

et al. 2019

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Characterization of super‐enhancer‐associated functional lncRNAs acting as ceRNAs in ESCC

et al. 2020

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Long noncoding RNAs (lncRNAs) have important regulatory roles in cancer biology. Although some lncRNAs have well‐characterized functions, the vast majority of this class of molecules remains functionally uncharacterized. To systematically pinpoint functional lncRNAs, a computational approach was proposed for identification of lncRNA‐mediated competing endogenous RNAs (ceRNAs) through combining global and local regulatory direction consistency of expression. Using esophageal squamous cell carcinoma (ESCC) as model, we further identified many known and novel functional lncRNAs acting as ceRNAs (ce‐lncRNAs). We found that most of them significantly regulated the expression of cancer‐related hallmark genes. These ce‐lncRNAs were significantly regulated by enhancers, especially super‐enhancers (SEs). Landscape analyses for lncRNAs further identified SE‐associated functional ce‐lncRNAs in ESCC, such as HOTAIR, XIST, SNHG5, and LINC00094. THZ1, a specific CDK7 inhibitor, can result in global transcriptional downregulation of SE‐associated ce‐lncRNAs. We further demonstrate that a SE‐associated ce‐lncRNA, LINC00094 can be activated by transcription factors TCF3 and KLF5 through binding to SE regions and promoted ESCC cancer cell growth. THZ1 downregulated expression of LINC00094 through inhibiting TCF3 and KLF5. Our data demonstrated the important roles of SE‐associated ce‐lncRNAs in ESCC oncogenesis and might serve as targets for ESCC diagnosis and therapy.

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Transcriptome of miRNA during inhibition of Bombyx mori nuclear polyhedrosis virus by geldanamycin in BmN cells

Zhao

Yin

Shen

et al. 2022

Arch Insect Biochem Physiol

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Bombyx mori nuclear polyhedrosis virus (BmNPV) is one of several viruses that cause great harm to the sericulture industry, and its pathogenic mechanism is still being explored. Geldanamycin (GA), a kind of HSP90 inhibitor, has been verified to suppress BmNPV proliferation. However, the molecular mechanism by which GA inhibits BmNPV is unclear. MicroRNAs (miRNAs) have been shown to play a key role in regulating virus proliferation and host‐pathogen interactions. In this study, BmN cells infected with BmNPV were treated by GA and DMSO for 72 h, respectively, then transcriptome analysis of miRNA was performed from the GA group and the control group. As a result, a total of 29 miRNAs were differentially expressed (DE), with 13 upregulated and 16 downregulated. Using bioinformatics analysis, it was found that the target genes of DEmiRNAs were involved in ubiquitin‐mediated proteolysis, phagosome, proteasome, endocytosis pathways, and so on. Six DEmiRNAs were verified by quantitative reverse‐transcription polymerase chain reaction. DElong noncoding RNA (DElncRNA)–DEmiRNA–messenger RNA (mRNA) regulatory networks involved in apoptosis and immune pathways were constructed in GA‐treated BmN cells, which included 12 DEmiRNA, 132 DElncRNA, and 69 mRNAs. This regulatory network enriched the functional role of miRNA in the BmNPV‐silkworm interactions and improved our understanding of the molecular mechanism of HSP90 inhibitors on BmNPV proliferation.

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Enhancer Control of MicroRNA miR-155 Expression in Epstein-Barr Virus-Infected B Cells

Cited by 44 publications

References 51 publications

Epstein-Barr Virus Latent Membrane Protein 1 Regulates Host B Cell MicroRNA-155 and Its Target FOXO3a via PI3K p110α Activation

Epstein-Barr Virus Latent Membrane Protein 1 Regulates Host B Cell MicroRNA-155 and Its Target FOXO3a via PI3K p110α Activation

Characterization of super‐enhancer‐associated functional lncRNAs acting as ceRNAs in ESCC

Transcriptome of miRNA during inhibition of Bombyx mori nuclear polyhedrosis virus by geldanamycin in BmN cells

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