Similar Datasets
Project description:Alveolar macrophages (AMs) form the first defense line against various respiratory pathogens, and their immune response has a profound impact on the outcome of respiratory infection. Enhancer of zeste homolog 2 (EZH2), which catalyzes the trimethylation of H3K27 for epigenetic repression, has gained increasing attention for its immune regulation function, yet its exact function in AMs remains largely obscure. Using porcine 3D4/21 AM cells as a model, we characterized the transcriptomic and epigenomic alterations after the inhibition of EZH2. We found that the inhibition of EZH2 causes transcriptional activation of numerous immune genes and inhibits the subsequent infection by influenza A virus. Interestingly, specific families of transposable elements, particularly endogenous retrovirus elements (ERVs) and LINEs which belong to retrotransposons, also become derepressed. While some of the derepressed ERV families are pig-specific, a few ancestral families are known to be under EZH2-mediated repression in humans. Given that derepression of ERVs can promote innate immune activation through "viral mimicry", we speculate that ERVs may also contribute to the coinciding immune activation in AMs after the inhibition of EZH2. Overall, this study improves the understanding of the EZH2-related immune regulation in AMs and provides novel insights into the epigenetic regulation of retrotransposons in pigs.
| S-EPMC9917017 | biostudies-literature
Project description:Alveolar macrophages (AMs) form the first defense line against a variety of respiratory pathogens, and their immune response has profound impact on the outcome of respiratory infection. It is of critical importance to clarify the immune regulation in AMs. Enhancer of Zeste Homolog 2 (EZH2), which catalyzes the trimethylation of H3K27 for epigenetic repression, has gained increasing attentions about their roles in immune regulation. However, the molecular mechanism underlying the immune regulation role of EZH2 in AMs remains largely unclear. Using porcine 3D4/21 alveolar macrophage cells as model, this study combined transcriptomic and epigenomic techniques to decipher the molecular function of EZH2 in AMs. Transcriptomic comparison revealed that inhibition of EZH2 in AMs causes transcriptional activation of dozens of immune genes which indicates an enhanced antiviral state, and as expected, we found that the infection of influenza A viruses can be remarkably affected. Interestingly, about one hundred families of transposable elements, particularly LTRs/ERVs and LINEs which belong to retrotransposons, get derepressed after EZH2 inhibition. Given that derepression of ERVs promotes innate immune activation in many tumors through the “viral mimicry” mechanism, the derepression of retrotransposon in AMs may also contribute to the coincided immune activation after EZH2 inhibition. Overall, this study improves the mechanistical understanding on the EZH2-dependent immune regulation in AMs and provides novel insights for the epigenetic regulation of retrotransposons in pigs.
2023-02-15 | GSE221476 | GEO
Project description:Alveolar macrophages (AMs) form the first defense line against a variety of respiratory pathogens, and their immune response has profound impact on the outcome of respiratory infection. It is of critical importance to clarify the immune regulation in AMs. Enhancer of Zeste Homolog 2 (EZH2), which catalyzes the trimethylation of H3K27 for epigenetic repression, has gained increasing attentions about their roles in immune regulation. However, the molecular mechanism underlying the immune regulation role of EZH2 in AMs remains largely unclear. Using porcine 3D4/21 alveolar macrophage cells as model, this study combined transcriptomic and epigenomic techniques to decipher the molecular function of EZH2 in AMs. Transcriptomic comparison revealed that inhibition of EZH2 in AMs causes transcriptional activation of dozens of immune genes which indicates an enhanced antiviral state, and as expected, we found that the infection of influenza A viruses can be remarkably affected. Interestingly, about one hundred families of transposable elements, particularly LTRs/ERVs and LINEs which belong to retrotransposons, get derepressed after EZH2 inhibition. Given that derepression of ERVs promotes innate immune activation in many tumors through the “viral mimicry” mechanism, the derepression of retrotransposon in AMs may also contribute to the coincided immune activation after EZH2 inhibition. Overall, this study improves the mechanistical understanding on the EZH2-dependent immune regulation in AMs and provides novel insights for the epigenetic regulation of retrotransposons in pigs.
2023-02-15 | GSE221478 | GEO
Project description:Alveolar macrophages (AMs) form the first defense line against a variety of respiratory pathogens, and their immune response has profound impact on the outcome of respiratory infection. It is of critical importance to clarify the immune regulation in AMs. Enhancer of Zeste Homolog 2 (EZH2), which catalyzes the trimethylation of H3K27 for epigenetic repression, has gained increasing attentions about their roles in immune regulation. However, the molecular mechanism underlying the immune regulation role of EZH2 in AMs remains largely unclear. Using porcine 3D4/21 alveolar macrophage cells as model, this study combined transcriptomic and epigenomic techniques to decipher the molecular function of EZH2 in AMs. Transcriptomic comparison revealed that inhibition of EZH2 in AMs causes transcriptional activation of dozens of immune genes which indicates an enhanced antiviral state, and as expected, we found that the infection of influenza A viruses can be remarkably affected. Interestingly, about one hundred families of transposable elements, particularly LTRs/ERVs and LINEs which belong to retrotransposons, get derepressed after EZH2 inhibition. Given that derepression of ERVs promotes innate immune activation in many tumors through the “viral mimicry” mechanism, the derepression of retrotransposon in AMs may also contribute to the coincided immune activation after EZH2 inhibition. Overall, this study improves the mechanistical understanding on the EZH2-dependent immune regulation in AMs and provides novel insights for the epigenetic regulation of retrotransposons in pigs.
2023-02-15 | GSE221477 | GEO
Project description:Inhibition of EZH2 causes retrotransposon derepression and immune activation in porcine lung alveolar macrophages.
| PRJNA914630 | ENA
Project description:Inhibition of EZH2 causes retrotransposon derepression and immune activation in porcine lung alveolar macrophages [ChIP-seq]
| PRJNA914633 | ENA
Project description:Inhibition of EZH2 causes retrotransposon derepression and immune activation in porcine lung alveolar macrophages [polyA-enriched RNA-seq]
| PRJNA914632 | ENA
Project description:Inhibition of EZH2 causes retrotransposon derepression and immune activation in porcine lung alveolar macrophages [rRNA-depleted RNA-seq]
| PRJNA914634 | ENA
Project description:BackgroundCurrently, an in vitro immunogenicity screening system for the immunological assessment of potential porcine reproductive and respiratory syndrome virus (PRRSV) vaccine candidates is highly desired. Thus, in the present study, two genetically divergent PRRSVs were characterized in vitro and in vivo to identify an in vitro system and immunological markers that predict the host immune response. Porcine alveolar macrophages (PAMs) and peripheral blood mononuclear cells (PBMCs) collected from PRRSV-negative pigs were used for in vitro immunological evaluation, and the response of these cells to VR2332c or JA142c were compared with those elicited in pigs challenged with the same viruses.ResultsCompared with VR2332c or mock infection, JA142c induced increased levels of type I interferons and pro-inflammatory cytokines (TNF-α, IL-1α/β, IL-6, IL-8, and IL-12) in PAMs, and these elevated levels were comparable to the cytokine induction observed in PRRSV-challenged pigs. Furthermore, significantly greater numbers of activated CD4+ T cells, type I helper T cells, cytotoxic T cells and total IFN-γ+ cells were observed in JA142c-challenged pigs than in VR2332c- or mock-challenged pigs.ConclusionsBased on these results, the innate immune response patterns (particularly IFN-α, TNF-α and IL-12) to specific PRRSV strains in PAMs might reflect those elicited by the same viruses in pigs.
| S-EPMC6278023 | biostudies-literature
Project description:Polycomb repressive complex 2 has a critical role in the maintenance of bivalent promoters and is often perturbed in cancer, including neuroendocrine tumors. In this study, we investigated the susceptibility of Merkel cell carcinoma (MCC), a neuroendocrine carcinoma of the skin, to inhibitors of the Polycomb repressive complex 2 catalytic subunit EZH2. We show that a subset of MCC cell lines is sensitive to EZH2 inhibitor-induced cell viability loss. We find that inhibitor treatment of susceptible cells derepresses the Polycomb repressive complex 2 target SIX1, a transcription factor in the PAX-SIX-EYA-DACH network normally involved in inner ear hair cell development, and that PAX-SIX-EYA-DACH network transcription factors are critical contributors to EZH2 inhibitor-induced MCC cell viability loss. Furthermore, we show the EZH2 inhibitor tazemetostat slows the growth of MCC xenografts and derepresses SIX1 and its downstream inner ear transcriptional target MYO6 in vivo. We propose that EZH2 inhibition in MCC leads to SIX1 derepression with dysregulation of hearing-related transcriptional programs and growth inhibition. This study provides evidence that MCC tumors may be specifically susceptible to EZH2 inhibitors, while giving mechanistic insight into the transcriptional programs these inhibitors perturb in MCC, and potentially in other neuroendocrine cancers.
| S-EPMC9492898 | biostudies-literature