Mi-2β knockout enhanced response of B16F10 cells to IFN-γ
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE151640 | GEO | 2023/05/23
REPOSITORIES: GEO
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Project description:Mi-2β knockout enhanced response of B16F10 cells to IFN-γ
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Project description:Recent development of new immune checkpoint inhibitors has been particularly successfully in cancer treatment, but still the majority patients fail to benefit. Converting resistant tumors to immunotherapy sensitivity will provide a significant improvement in patient outcome. Here we identify Mi-2β as a key melanoma-intrinsic effector regulating the adaptive anti-tumor immune response. Genetically engineered mouse melanoma studies indicate that loss of Mi-2β rescued the immune response to immunotherapy in vivo. Mechanistically, ATAC-seq indicate that Mi-2β controlled the accessibility of IFN-γ-stimulated genes (ISGs). Mi-2β bound to EZH2 and promote K510 methylation of EZH2 and subsequently activate the trimethylation of H3K27 to inhibit the transcription of ISGs. Finally, we develop an Mi-2β-targeted inhibitor, Z36-MP5, which targeted inhibition of Mi-2β ATPase activity and recovered ISG transcription. Consequently, Z36-MP5 efficiently induce a response to immunotherapy in otherwise resistant melanomas. Our work provides a potential therapeutic strategy to convert immunotherapy resistant melanomas to sensitive ones.
2024-02-19 | GSE255782 | GEO
Project description:Keratinocytes respond to environmental signals by eliciting induction of genes that preserve skin’s integrity. Here we show that the transcriptional response to stress signaling is supported by short-lived epigenetic changes. Comparison of chromatin accessibility and transcriptional changes induced by barrier disruption or by loss of the nucleosome remodeler Mi-2β identified their striking convergence in mouse and human keratinocytes. Mi-2β directly repressed genes induced by barrier disruption by restricting AP1-enriched promoter-distal sites, occupied by Mi-2β and JUNB at steady state and by c-JUN after Mi-2β depletion or stress signaling. Barrier disruption led to a modest reduction in Mi-2β expression and a further selective reduction of Mi-2β localization at stress response genes possibly through competition with activated c-JUN. Consistent with a repressive role at stress response genes, genetic ablation of Mi-2β did not prevent re-establishment of barrier integrity but was required for return to homeostasis. Thus a competition between Mi-2β repressive and activating AP1 complexes may permit rapid transcriptional response to and resolution from stress signaling.
2019-12-03 | GSE139685 | GEO
Project description:For identification of Mi-2β-interacting proteins, B16F10 cells (1 × 108) were collected and washed three times with PBS and lysed in lysis buffer on ice for 30 min. Cell lysates were collected and then isolated over night by anti-Mi-2β magnetic agarose beads. The anti-Mi-2β magnetic agarose beads were collected and washed three times with PBS. The prepared protein samples were incubated with sample buffer for 15 min at 100 °C, and then separated by SDS-PAGE (10%). The gel was immersed in staining solution (0.3% Coomassie blue, 45% methanol, 10% glacial acetic acid and 45% dH2O) on shaker for 30 min, followed by incubation in destaining solution (20% methanol, 10% glacial acetic acid, and 70% dH2O) on the shaker overnight. The bands were excised and sent to Biological Mass Spectrometry Facility of Shanghai Applied Protein Technology Co., Ltd for protein identification.
2024-02-18 | PXD049467 |
Project description:Mi-2β promotes immune evasion in melanoma by activating EZH2 methylation
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Project description:Functional interactions between Mi-2β and AP1 complexes control response and recovery from barrier disruption
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Project description:The Activating Protein 2β transcription factor (TFAP2B; AP-2β) is a marker for both lobular and molecular apocrine/HER2-E breast cancers, despite these tumours having very different prognoses. We show that simultaneous expression of both AP-2β and the estrogen receptor (ESR1, ER) marks well differentiated, low proliferation cells that are characteristic of luminal A lobular tumours, but loss of ER expression occurs when the tumour cells progress to molecular apocrine tumours. To discover potential explanations for this behaviour we performed chromatin immunoprecipitation sequencing (ChIP-seq) for AP-2β, AR, GATA3, FOXA1 and H3K27 acetylation in ER-negative MDA-MB-453 breast cancer cells. We find that all four transcription factors frequently bind to the same enhancers and that these enhancers are more likely to be active when AP-2β is present. Molecular apocrine genes are significantly more likely to have enhancers bound to all four transcription factors flanked by H3K27 acetylation. When AP-2β binds separately from the other factors, it binds close to the transcription start site, where it shows very high enrichment for H3K27 acetylation. AP-2 family proteins activate transcription by recruiting CITED proteins and p300/CBP. Since AR, FOXA1 and GATA3 are themselves able to recruit histone acetyl-transferases, we infer that AP-2β regulates the activity of those histone acetyl-transferases. We propose that this broad fundamental role in transcription explains the contradictory functions, both oncogenic and tumour suppressing, that have been assigned to AP-2 family members in previous studies on cancer.
2023-12-31 | GSE207472 | GEO
Project description:The Activating Protein 2β transcription factor (TFAP2B; AP-2β) is a marker for both lobular and molecular apocrine/HER2-E breast cancers, despite these tumours having very different prognoses. We show that simultaneous expression of both AP-2β and the estrogen receptor (ESR1, ER) marks well differentiated, low proliferation cells that are characteristic of luminal A lobular tumours, but loss of ER expression occurs when the tumour cells progress to molecular apocrine tumours. To discover potential explanations for this behaviour we performed chromatin immunoprecipitation sequencing (ChIP-seq) for AP-2β, AR, GATA3, FOXA1 and H3K27 acetylation in ER-negative MDA-MB-453 breast cancer cells. We find that all four transcription factors frequently bind to the same enhancers and that these enhancers are more likely to be active when AP-2β is present. Molecular apocrine genes are significantly more likely to have enhancers bound to all four transcription factors flanked by H3K27 acetylation. When AP-2β binds separately from the other factors, it binds close to the transcription start site, where it shows very high enrichment for H3K27 acetylation. AP-2 family proteins activate transcription by recruiting CITED proteins and p300/CBP. Since AR, FOXA1 and GATA3 are themselves able to recruit histone acetyl-transferases, we infer that AP-2β regulates the activity of those histone acetyl-transferases. We propose that this broad fundamental role in transcription explains the contradictory functions, both oncogenic and tumour suppressing, that have been assigned to AP-2 family members in previous studies on cancer.
2023-12-31 | GSE207230 | GEO
Project description:Coordinated induction but also repression of genes is key to normal differentiation. Although the role of lineage-specific transcription regulators has been extensively studied, their functional integration with chromatin remodelers, one of the key enzymatic machineries that control chromatin accessibility, remains ill-defined. Here we investigate the role of Mi-2b, a SNF-2-like nucleosome remodeler and key component of the Nucleosome Remodeling Deacetylase (NuRD) complex in early B cells. Inactivation of Mi-2b arrested differentiation at the large pre-B cell stage and caused de-repression of cell adhesion and cell migration signaling factors by increasing chromatin access at poised enhancers and chromosome architectural elements. Mi-2b also supported IL-7R signaling, survival and proliferation by repressing negative effectors of this pathway. Importantly, over-expression of Bcl2, a mitochondrial pro-survival factor and target of IL-7R signaling, partly rescued the differentiation block caused by Mi-2b loss. Mi-2b stably associated with chromatin sites that harbor binding motifs for IKAROS and EBF1 and physically associated with these transcription factors both on and off chromatin. Notably, Mi-2b shared loss-of-function cellular and molecular phenotypes with IKAROS and EBF1 albeit in a distinct fashion. Thus the nucleosome remodeler Mi-2b promotes pre-B cell differentiation by providing repression capabilities to distinct lineage-specific transcription factor-based regulatory networks.
2019-05-15 | GSE130315 | GEO
Project description:Environmental challenges to epithelial cells trigger gene expression changes that elicit context-appropriate immune responses. Here we show that the chromatin remodeler Mi-2β controls epidermal homeostasis by holding genes involved in keratinocyte and immune-cell activation at an inactive state. Mi-2β depletion caused rapid deployment of both a pro-inflammatory and an immunosuppressive response in the skin. A key target of Mi-2β in keratinocytes was the pro-inflammatory cytokine Thymic Stromal Lymphopoietin (TSLP). Loss of TSLPR signaling specifically in regulatory T cells (Treg) prevented their activation and permitted rapid progression from a skin pro-inflammatory response to a lethal systemic condition. Thus, in addition to their well-characterized role in pro-inflammatory responses, keratinocytes also directly support immune-suppressive responses that are critical for re-establishing organismal homeostasis.
2017-01-09 | GSE90573 | GEO