MAPK-induced miR-29 targets MAFG and suppresses melanoma progression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA625032 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11539515_1.fastq.gz | Fastqsanger.gz | |||
| SRR11539515_2.fastq.gz | Fastqsanger.gz | |||
| SRR11539516_1.fastq.gz | Fastqsanger.gz | |||
| SRR11539516_2.fastq.gz | Fastqsanger.gz | |||
| SRR11539517_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 60 |
Similar Datasets
Project description:The tumor suppressive miR-29 family of microRNAs is encoded by two clusters, miR-29b1~a and miR-29b2~c, and is regulated by several oncogenic and tumor suppressive stimuli. Here we investigated whether oncogenic MAPK hyperactivation regulates miR-29 abundance and how this signaling axis impacts melanoma development. Using mouse embryonic fibroblasts and human melanocytes, we found that oncogenic MAPK signaling stimulates p53-independent and p53-dependent transcription of pri-miR-29b1~a and pri-miR-29b2~c, respectively. Expression analyses revealed that while pri-miR-29a~b1 remains elevated, pri-miR-29b2~c levels decrease during melanoma progression. Using a rapid mouse modeling platform, we showed that inactivation of miR-29 in vivo accelerates the development of frank melanomas and decreases overall survival. We identified MAFG as a relevant miR-29 target that has oncogenic potential in melanocytes and is required for growth of melanoma cells. Our findings suggest that MAPK-driven miR-29 induction constitutes a tumor suppressive barrier by targeting MAFG, which is overcome by attenuation of miR-29b2~c expression.
2023-04-10 | GSE148552 | GEO
Project description:The miR-29 family of microRNAs is encoded by two clusters, miR-29b1~a and miR-29b2~c, and is regulated by several oncogenic and tumor suppressive stimuli. While in vitro evidence suggests a tumor suppressor role for miR-29 in melanoma, the mechanisms underlying its deregulation and contribution to melanomagenesis have remained elusive. Using various in vitro systems, we show that oncogenic MAPK signaling paradoxically stimulates transcription of pri-miR-29b1~a and pri-miR-29b2~c, the latter in a p53-dependent manner. Expression analyses in melanocytes, melanoma cells, nevi, and primary melanoma revealed that pri-miR-29b2~c levels decrease during melanoma progression. Inactivation of miR-29 in vivo with a miRNA sponge in a rapid melanoma mouse model resulted in accelerated tumor development and decreased overall survival, verifying tumor suppressive potential of miR-29 in melanoma. Through integrated RNA sequencing, target prediction, and functional assays, we identified the transcription factors MAFG and MYBL2 as bona fide miR-29 targets in melanoma. Our findings suggest that attenuation of miR-29b2~c expression promotes melanoma development, at least in part, by derepressing MAFG and MYBL2.
| S-EPMC8003541 | biostudies-literature
Project description:While common mutations in potent proto-oncogenes and tumor suppressors induce melanoma formation, no recurrent mutations associated with the late stages of melanomagenesis have been identified. Instead, non-mutational mechanisms such as the deregulation of transcriptiona or epigenetic programs typically promote the malignant progression and metastasis of melanoma. We have previously identified the small MAFG transcription factor MAFG as a critical target of the melanoma suppressor miRNA miRN-29, prompting an in-depth evaluation of the role of MAFG in melanoma. MAFG expression is elevated in melanoma compared to melanocytes and increases with tumor stage. Ectopic expression of MAFG in human melanocytes and melanoma cells enhances proliferation in virto and promotes melanoma growth in vivo. Moreover, MAFG overexpression in BRAFV600E; PTEN+/- mice accelerated melanomagenesis, significantly shortening overall survival. Despite being a critical NRF2 dimerization partner, NRF2 was dispensable for the effects of MAFG. Moreover, MAFG overexpression in melanoma had no effect on the activity of NRF2 transcriptional reporters, nor did it induce transcriptional programs associated with NRF2. RNA sequencing and pathway analysis revealed MAFG-mediated effects on melanoma-associated processes such as pigmentation. Indeed, MAFG downregulated MITF and its target genes in the pigmentation pathway in melanoma cells. We next analyzed the connection between MAFG and MITF and found that MAFG binds to MITF to impede its binding to melanocytic differentiation genes, thus promoting a less differentiated and more aggressive phenotype. Our study establishes MAFG as a potent driver of melanoma development through the relocation of MITF.
2024-10-09 | GSE274810 | GEO
Project description:MafF-/-: MafG+/+: MafK-/- mice are viable, while MafF-/-: MafG-/-: MafK-/- mice are embryonic lethal. To get an insight into the cause of the lethality of small Maf triple knockout mice, transcriptome analysis was performed using whole embyos of MafF-/-: MafG-/-: MafK-/- at E10.5 and those of MafF-/-: MafG+/+: MafK-/- at E9.5 or E10.5. Because MafF-/-: MafG-/-: MafK-/- embryos exhibit growth retardation, the gene expression profile of MafF-/-: MafG-/-: MafK-/- embryos at E10.5 was compared with that of MafF-/-: MafG+/+: MafK-/- embyos at E9.5. The gene expression profile of MafF-/-: MafG+/+: MafK-/- embryos at E10.5 was also examined as an alternative control. Total RNA was prepared from pooled three embryos for each sample.
2012-01-09 | E-GEOD-29558 | biostudies-arrayexpress
Project description:MafF-/-: MafG+/+: MafK-/- mice are viable, while MafF-/-: MafG-/-: MafK-/- mice are embryonic lethal. To get an insight into the cause of the lethality of small Maf triple knockout mice, transcriptome analysis was performed using whole embyos of MafF-/-: MafG-/-: MafK-/- at E10.5 and those of MafF-/-: MafG+/+: MafK-/- at E9.5 or E10.5. Because MafF-/-: MafG-/-: MafK-/- embryos exhibit growth retardation, the gene expression profile of MafF-/-: MafG-/-: MafK-/- embryos at E10.5 was compared with that of MafF-/-: MafG+/+: MafK-/- embyos at E9.5. The gene expression profile of MafF-/-: MafG+/+: MafK-/- embryos at E10.5 was also examined as an alternative control.
2012-01-09 | GSE29558 | GEO
Project description:We report MAFG recruitment to ARE elements in astrocytes during EAE compared to naïve mice Multiple sclerosis (MS) is an autoimmune neurologic disease leading to demyelination and neurologic dysfunction controlled by both genetic and environmental factors. In addition to CNS-infiltrating immune cells, CNS-resident cells, such as astrocytes, are thought to play an important role in MS pathogenesis. However, a comprehensive understanding of the extent to which gene expression is disrupted in astrocytes is not known. Here, we implement single-cell RNA sequencing, in vivo genetic perturbations, cell-specific RNA profiling by Ribotag, as well as single-cell RNA sequencing of human MS patient samples to identify a transcriptional regulatory network in astrocytes that controls the pathogenesis of EAE and potentially, MS. We defined an astrocyte subpopulation characterized by expression of the small Maf protein, MAFG, which represses NRF2-driven antioxidant mechanisms and promotes EAE pathogenesis. Mechanistically, MAFG suppresses NRF2-dependent antioxidant genetic programs by cooperating with its cofactor, MAT2a, to promote DNA methylation in the context of CNS inflammation, which in turn increases pathogenic signaling processes in astrocytes. MAFG/MAT2a astrocytes are controlled by GM-CSF signaling, which drives EAE pathogenesis and MAFG expression. MAFG is activated in astrocytes derived from MS patients, which are characterized by DNA methylation programs, pro-inflammatory signaling processes including GM-CSF signaling, and repressed NRF2 activation. Together, these data create a transcriptional and epigenetic framework to analyze CNS inflammation in MS and may provide new therapeutic targets.
2020-02-12 | GSE129607 | GEO
Project description:Although majority of the genes linked to pediatric cataract exhibit lens fiber cell-enriched expression, our understanding of gene regulation in these cells is limited to function of just eight transcription factors and largely in the context of crystallins. Here, we identify small Maf transcription factors MafG and MafK as regulators of several non-crystallin human cataract genes in fiber cells and establish their significance to cataract. We applied a bioinformatics tool for cataract gene discovery iSyTE to identify MafG and its co-regulators in the lens, and generated various null-allelic combinations of MafG:MafK mouse mutants for phenotypic and molecular analysis. By age 4-months, MafG-/-:MafK+/- mutants exhibit lens defects that progressively develop into cataract. High-resolution phenotypic characterization of MafG-/-:MafK+/- lens reveals severe defects in fiber cells, while microarrays-based expression profiling identifies 97 differentially regulated genes (DRGs). Integrative analysis of MafG-/-:MafK+/- lens-DRGs with 1) binding-motifs and genomic targets of small Mafs and their regulatory partners, 2) iSyTE lens-expression data, and 3) interactions between DRGs in the String database, unravels a detailed small Maf regulatory network in the lens, several nodes of which are linked to human cataract. This analysis prioritizes 36 highly promising candidates from the original 97 DRGs. Significantly, 8/36 (22%) DRGs are associated with cataracts in human (GSTO1, MGST1, SC4MOL, UCHL1) or mouse (Aldh3a1, Crygf, Hspb1, Pcbd1), suggesting a multifactorial etiology that includes elevation of oxidative stress. These data identify MafG and MafK as new cataract-associated candidates and define their function in regulating largely non-crystallin genes linked to mouse and human cataract. Microarray comparision of lenses from mixed background (129Sv/J, C57BL/6J, and ICR) control (MafG+/-:MafK+/-; no-cataract) and compound (MafG-/-:MafK+/-; cataract) mouse mutants
2015-05-01 | E-GEOD-65500 | biostudies-arrayexpress
Project description:Specific bile acids are potent signaling molecules that modulate metabolic pathways affecting lipid, glucose and bile acid homeostasis, and the microbiota. Bile acids are synthesized from cholesterol in the liver, and the key enzymes involved in bile acid synthesis (Cyp7a1, Cyp8b1) are regulated transcriptionally by the nuclear receptor FXR. We have identified an FXR-regulated pathway upstream of a transcriptional repressor that controls multiple bile acid metabolism genes. We identify MafG as an FXR target gene and show that hepatic MAFG overexpression represses genes of the bile acid synthetic pathway and modifies the biliary bile acid composition. In contrast, loss-of-function studies using MafG(+/-) mice causes de-repression of the same genes with concordant changes in biliary bile acid levels. Finally, we identify functional MafG response elements in bile acid metabolism genes using ChIP-seq analysis. Our studies identify a molecular mechanism for the complex feedback regulation of bile acid synthesis controlled by FXR
2016-02-04 | GSE77507 | GEO
Project description:Disrupting PD-1/PD-L1 interaction rejuvenates antitumor immunity. Clinical successes by blocking PD-1/PD-L1 binding have grown across wide-ranging cancer histologies, but innate therapy resistance is evident in the majority of treated patients1. Cancer cells can express robust surface levels of PD-L1 to tolerize tumor-specific T cells, but regulation of PD-L1 protein levels in the cancer cell is poorly understood. Quasi-mesenchymal tumor cells up-regulate PD-L1/L2 and induce an immune-suppressive microenvironment, including expansion of M2-like macrophages and regulatory T cells and exclusion of CD8+ T-cell infiltration2. Targeted therapy, including MAPK inhibitor therapy in melanoma, leads to quasi-mesenchymal transitions and resistance3, and both MAPK inhibitor treatment and mesenchymal signatures are associated with innate anti-PD-1 resistance4,5. Here we identify ITCH as an E3 ligase that downregulates tumor cell-surface PD-L1/L2 in PD-L1/L2-high cancer cells, including MAPK inhibitor-resistant melanoma, and suppresses acquired MAPK inhibitor resistance in and only in immune-competent mice. ITCH interacts with and poly-ubiquitinates PD-L1/L2, and ITCH deficiency increases cell-surface PD-L1/L2 expression and reduces T cell activation. Mouse melanoma tumors grow faster with Itch knockdown only in syngeneic hosts but not in immune-deficient mice. MAPK inhibitor therapy induces tumor cell-surface PD-L1 expression in murine melanoma, recapitulating the responses of clinical melanoma3, and this induction is more robust with Itch knockdown. Notably, suppression of ITCH expression first elicits a shift toward an immune-suppressive microenvironment and then accelerates resistance development. These findings collectively identify ITCH as a critical negative regulator of PD-L1 tumor cell-surface expression and provide insights into previously unexplained role of PD-L1 in adaptive resistance to therapy.
2022-03-31 | MSV000089180 | MassIVE