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Interferon Regulatory Factor 4 Modulates Epigenetic Silencing and Cancer-Critical Pathways in Melanoma Cells

ABSTRACT: Interferon Regulatory Factor 4 Modulates Epigenetic Silencing and Cancer-Critical Pathways in Melanoma Cells

PROVIDER: PRJNA1023214 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26257600.fastq.gz	Fastqsanger.gz
	SRR26257601.fastq.gz	Fastqsanger.gz
	SRR26257602.fastq.gz	Fastqsanger.gz
	SRR26257603.fastq.gz	Fastqsanger.gz
	SRR26257604.fastq.gz	Fastqsanger.gz

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Interferon Regulatory Factor 4 Modulates Epigenetic Silencing and Cancer-Critical Pathways in Melanoma Cells

Project description:Interferon Regulatory Factor 4 (IRF4) is a transcription factor initially identified as a key controller in lymphocyte differentiation and function, and subsequently as a dependency factor and therapy target in lymphocyte-derived cancers. In melanocytes, IRF4 takes part in the regulation of pigmentation. While numerous genetic studies have implicated IRF4 also in melanoma skin cancers, how IRF4 contributes to melanoma has remained largely elusive. In this study, we first confirmed that not only IRF4 expression is common in melanoma, but also IRF4 can act as a dependency factor for melanoma cells. Furthermore, to discover the functions of IRF4 in melanoma cells, we analyzed IRF4 target genes, which pointed to IRF4 as an upstream regulator of epigenetic silencing. Accordingly, we show that IRF4 regulates the expression of essential factors for DNA methylation (DNMT1, DNMT3B, UHFR1) and for repressive histone H3 lysine 27 methylation (EZH2), and consequently, the levels of the corresponding methylation marks. Moreover, expression of several tumor suppressor genes known to be silenced by these epigenetic modifications are regulated by IRF4. These include cyclin-dependent kinase inhibitors, PI3K pathway regulator PTEN, and primary cilium component WDR19. As a result, IRF4-dependent epigenetic regulation in melanoma cells modulates the activity of key oncogenic pathways, such as WNT/b-Catenin and PI3K-AKT, impacting on cell proliferation and survival. Moreover, IRF4 modulates the activity of pertinent epigenetic drugs in melanoma cells, encouraging further studies on the therapeutic targeting of IRF4 in melanoma.

2024-07-01 | GSE244460 | GEO

Interferon regulatory factor 4 modulates epigenetic silencing and cancer-critical pathways in melanoma cells.

Project description:Interferon regulatory factor 4 (IRF4) was initially identified as a key controller in lymphocyte differentiation and function, and subsequently as a dependency factor and therapy target in lymphocyte-derived cancers. In melanocytes, IRF4 takes part in pigmentation. Although genetic studies have implicated IRF4 in melanoma, how IRF4 functions in melanoma cells has remained largely elusive. Here, we confirmed prevalent IRF4 expression in melanoma and showed that high expression is linked to dependency in cells and mortality in patients. Analysis of genes activated by IRF4 uncovered, as a novel target category, epigenetic silencing factors involved in DNA methylation (DNMT1, DNMT3B, UHRF1) and histone H3K27 methylation (EZH2). Consequently, we show that IRF4 controls the expression of tumour suppressor genes known to be silenced by these epigenetic modifications, for instance cyclin-dependent kinase inhibitors CDKN1A and CDKN1B, the PI3-AKT pathway regulator PTEN, and primary cilium components. Furthermore, IRF4 modulates activity of key downstream oncogenic pathways, such as WNT/β-catenin and AKT, impacting cell proliferation and survival. Accordingly, IRF4 modifies the effectiveness of pertinent epigenetic drugs on melanoma cells, a finding that encourages further studies towards therapeutic targeting of IRF4 in melanoma.

| S-EPMC11459048 | biostudies-literature

RNA editing modulates pathways critical to B cell lymphomagenesis

Project description:RNA editing modulates pathways critical to B cell lymphomagenesis

| PRJNA605715 | ENA

LNK suppresses interferon signaling in melanoma

Project description:LNK (SH2B3) is a key negative regulator of JAK-STAT signaling which has been extensively studied in malignant hematopoietic diseases. We found that LNK is significantly elevated in cutaneous melanoma; this elevation is correlated with hyperactive signaling of the RAS-RAF-MEK pathway. Elevated LNK enhances cell growth and survival in adverse conditions. Forced expression of LNK inhibits signaling by interferon-STAT1 and suppresses interferon (IFN) induced cell cycle arrest and cell apoptosis. In contrast, silencing LNK expression by either shRNA or CRISPR-Cas9 potentiates the killing effect of IFN. The IFN-LNK signaling is tightly regulated by a negative feedback mechanism; melanoma cells exposed to IFN upregulate expression of LNK to prevent overactivation of this signaling pathway. Our study reveals an unappreciated function of LNK in melanoma and highlights the critical role of the IFN-STAT1-LNK signaling axis in this potentially devastating disease. LNK may be further explored as a potential therapeutic target for melanoma immunotherapy.

2019-04-29 | GSE127333 | GEO

Interferon-dependent signaling is critical for viral clearance in airway neutrophils

Project description:Interferon-dependent signaling is critical for viral clearance in airway neutrophils

| PRJNA948393 | ENA

Silencing of interferon regulatory factor gene 6 in melanoma.

Project description:BackgroundMethylation of a CpG island (CGI; a dense cluster of CpGs) located in the 5' region of a gene suppresses transcription of that gene. Interferon regulatory factor 6 (IRF6) is associated with the expression of interferon, which is used as an effective adjuvant therapy for melanoma, and is regarded as a tumor suppressor. However, little is known about the methylation status of the IRF6 gene in melanoma.ObjectiveThe purpose was to determine the methylation status of the CGI located in the 5' region of IRF6 (5' IRF6 CGI) in melanoma.MethodsQuantitative real-time methylation-specific PCR (RT-MSP) and bisulfite sequencing were performed to examine IRF6 gene methylation status. Quantitative real-time reverse transcription-PCR (RT-PCR) was performed to examine IRF6 expression.ResultsThe methylation level of the 5' IRF6 CGI was completely inversely correlated with cell sensitivity to interferon-β in eight examined melanoma cell lines. These methylation levels were high in the melanoma cell lines with suppression of IRF6 expression and were low in the cell lines with IRF6 expression. The methylation levels of the 5' IRF6 CGI ranged widely from 0.0% to 65.4% in 21 clinical melanoma samples but showed a narrow range of low levels between 0.0% to 7.2% in 24 clinical melanocytic nevus samples. These methylation levels were not associated with clinical parameters except for melanoma subtypes.ConclusionIRF6 is aberrantly silenced by DNA methylation of the 5' IRF6 CGI in melanoma. The methylation status of IRF6 is potentially associated with the sensitivity of melanoma to interferon.

| S-EPMC5587289 | biostudies-literature

Dexamethasone modulates immature neutrophils and interferon programming in severe COVID-19

Project description:Dexamethasone modulates immature neutrophils and interferon programming in severe COVID-19

| PRJNA662785 | ENA

Interleukin-4 modulates type I interferon to augment anti-tumour immunity

Project description:Interleukin-4 modulates type I interferon to augment anti-tumour immunity

| PRJNA1224251 | ENA

Nuclear RNAi Modulates Influenza A Virus Infectivity By Downregulating Type-I Interferon Response

Project description:The role of Argonaute (AGO) proteins and the RNA interference (RNAi) machinery in mammalian antiviral response has been debated. Therefore, we set out to investigate how mammalian RNAi impacts influenza A virus (IAV) infection. We demonstrate that IAV infection triggers nuclear accumulation of AGO2, which is directly facilitated by p53 activation. Mechanistically, we show that IAV induces nuclear AGO2 targeting of TRIM71, a proposed AGO2 E3 ligase, and type-I interferon-pathway genes for silencing. Hence, the RNAi machinery is highjacked by the virus to evade the immune system and support viral replication. We demonstrate that the FDA approved drug arsenic trioxide prevents nuclear AGO2:p53 accumulation, thereby increasing interferon response and decreasing viral replication in vitro and in a mouse model in vivo. Our data indicates that targeting the AGO2:p53-mediated silencing of innate immunity may offer a promising strategy to mitigate viral infections.

2025-03-13 | GSE271042 | GEO

IRF2BP2 Modulates the Crosstalk between Glucocorticoid and TNF Signaling

Project description:Here we have analyzed the role of interferon regulatory factor-2 binding protein-2 (IRF2BP2) in glucocorticoid and tumor necrosis factor alpha (TNF) signaling. We used ChIP-seq to analyze chromatin binding of IRF2BP2 in glucocorticoid (dexamethasone, dex) and vehicle treated HEK293 cells expressing GR (HEK293-GR). Furthermore, we used RNA-seq to analyze how silencing of IRF2BP2 modulates transcriptional responses to dex treatment in HEK293-GR cells, and dex, TNF and co-treatment (dex and TNF, DT) in A549 cells.

2019-06-03 | GSE124636 | GEO

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