METTL3/MYCN cooperation drives neural crest differentiation and provides therapeutic vulnerability in neuroblastoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1023241 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26263600_1.fastq.gz | Fastqsanger.gz | |||
| SRR26263600_2.fastq.gz | Fastqsanger.gz | |||
| SRR26263601_1.fastq.gz | Fastqsanger.gz | |||
| SRR26263601_2.fastq.gz | Fastqsanger.gz | |||
| SRR26263602_1.fastq.gz | Fastqsanger.gz |
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Project description:Neuroblastoma (NB) is a childhood cancer. Improper differentiation of developing trunk neural crest cells (tNCC) cause NB tumor formation in sympathetic nervous system. N6-methyladenosine (m6A) epitranscriptomic modification control post-transcriptional gene expression but the mechanism which recruit m6A methyltransferase complex to specific locus is less characterized. We explored if m6A epitranscriptome could fine tune gene regulation in migrating/differentiating tNCC. We uncovered m6A epitranscriptome based regulation of HOX gene expression in tNCC which contributes in their timely differentiation to sympathetic neurons. Posterior HOX genes are m6A modified in MYCN NB cells and tumors. We provided evidence that sustained overexpression of MYCN oncogene could drive METTL3 recruitment in subset of genes to create an undifferentiated state in tNCC. Our study suggests oncogenic transcription factor mediated modulation of m6A epitranscriptome could be a prevalent mechanism in other cancers. METTL3 depletion/inhibition induces DNA damage and differentiation in MYCN overexpressed cells. METTL3 inhibition increases vulnerability to the chemotherapeutic drug in MYCN-amplified Patient-derived xenografts (PDX) cells, suggesting METTL3 inhibition could be a potential therapeutic approach for NB.
2024-09-30 | GSE244473 | GEO
Project description:Neuroblastoma (NB) is the most common extracranial childhood cancer, caused by the improper differentiation of developing trunk neural crest cells (tNCC) in the sympathetic nervous system. The N6-methyladenosine (m6A) modification controls post-transcriptional gene expression but the mechanism by which the m6A methyltransferase complex METTL3/METTL14/WTAP is recruited to specific loci remains to be fully characterized. We explored whether the m6A epitranscriptome could fine-tune gene regulation in migrating/differentiating tNCCs. We demonstrate that the m6A modification regulates the expression of HOX genes in tNCCs, thereby contributing to their timely differentiation into sympathetic neurons. Furthermore, we show that posterior HOX genes are m6A-modified in MYCN-amplified neuroblastoma with reduced expression. In addition, we provide evidence that sustained overexpression of the MYCN oncogene in tNCC drives METTL3 recruitment to a specific subset of genes including posterior HOX genes, creating an undifferentiated state. Moreover, METTL3 depletion or inhibition induces DNA damage and differentiation of MYCN-overexpressing cells and increases vulnerability to chemotherapeutic drugs in MYCN-amplified patient-derived xenografts in vivo, suggesting METTL3 inhibition as a potential therapeutic approach for NB.
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Project description:The increased heme biosynthesis long observed in leukemia was previously of unknown significance. Heme, synthesized from porphyrin precursors, plays a central role in oxygen metabolism and mitochondrial function, yet little is known about its role in leukemogenesis. Here we show increased expression of heme biosynthetic genes, including UROD, only in pediatric AML with high MYCN expression. Both high UROD and MYCN expression predict poor overall survival and unfavorable outcomes in adult AML. Murine leukemic progenitors derived from hematopoietic progenitor cells (HPCs) overexpressing a MYCN cDNA (MYCN-HPC) require heme/porphyrin biosynthesis, accompanied by increased oxygen consumption, to fully engage in self-renewal and oncogenic transformation. Blocking heme biosynthesis reduced mitochondrial oxygen consumption and markedly suppressed self-renewal. Leukemic progenitors rely on balanced production of heme and heme intermediates, the porphyrins. Porphyrin homeostasis is required because absence of the porphyrin exporter, ABCG2, increased death of leukemic progenitors in vitro and prolonged the survival of mice transplanted with Abcg2-KO MYCN HPCs. Pediatric AML patients with elevated MYCN mRNA display strong activation of TP53 target genes. Abcg2-KO MYCN HPCs were rescued from porphyrin toxicity by p53 loss. This vulnerability was exploited to show that treatment with a porphyrin precursor, coupled with the absence of ABCG2, blocked MYCN-driven leukemogenesis in vivo thereby demonstrating, that porphyrin homeostasis is a pathway crucial to MYCN leukemogenesis. We used microarrays to compare the global transcription profiles of hematopoietic progenitor cells from wild-type and Abcg2-ko mice that after transduction with vector-alone or vector containing MYCN gene.
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Project description:MYCN amplification in neuroblastoma leads to aberrant expression of MYCN oncoprotein, which binds active genes promoting transcriptional amplification. Yet how MYCN coordinates transcription elongation to meet productive transcriptional amplification and which elongation machinery represents MYCN-driven vulnerability remain to be identified. We conducted a targeted screen of transcription elongation factors and identified the super elongation complex (SEC) as a unique vulnerability in MYCN-amplified neuroblastomas. MYCN directly binds EAF1 and recruits SEC to enhance processive transcription elongation. Depletion of EAF1 or AFF1/AFF4, another core subunit of SEC, leads to a global reduction in transcription elongation and elicits selective apoptosis of MYCN-amplified neuroblastoma cells. A combination screen reveals SEC inhibition synergistically potentiates the therapeutic efficacies of FDA-approved BCL2 antagonist ABT-199, in part due to suppression of MCL1 expression, both in MYCN-amplified neuroblastoma cells and in patient-derived xenografts. These findings identify disruption of the MYCN-SEC regulatory axis as a promising therapeutic strategy in neuroblastoma.
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Project description:The cooperation between MYCN and its cofactors WDR5 and G9a
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Project description:The cooperation between HAND2 and MYCN on DNA binding [HAND2-overexpression_ChIPseq]
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Project description:Many of the pro-tumorigenic functions of the oncogene MYCN are attributed to its regulation of global gene expression programs. Alternative splicing is another important regulator of gene expression and has been implicated in neuroblastoma development, however, the molecular mechanisms behind this remain unknown. We found that MYCN up-regulated the core spliceosomal protein, SNRPD3, in models of neuroblastoma initiation and progression. MYCN directly bound SNRPD3, and the protein arginine methyltransferase, PRMT5. RNA-sequencing revealed a global increase in the number of genes being differentially spliced when MYCN was overexpressed, while depletion of SNPRD3 in the presence of overexpressed MYCN was sufficient to induce additional increases in differential splicing, particularly genes involved in the cell cycle. SNRPD3 knockdown in the presence of MYCN was accompanied with marked loss of cell viability, suggesting that SNRPD3 maintains splicing balance for MYCN, and prevents detrimental differential splicing of cell cycle genes in neuroblastoma. Further analysis revealed BIRC5 and CDK10 to be among the topmost differentially spliced cell cycle genes, both of which play a role in the G2/M phase of the cell cycle. Flow cytometry analysis revealed that depletion of SNRPD3 resulted in G2/M cell cycle arrest. Furthermore, SNRPD3 was an oncogenic co-factor for MYCN in vitro and in vivo. As such, SNRPD3 represents a therapeutic vulnerability for neuroblastoma cells in the presence of high MYCN expression. Indeed, the PRMT5 inhibitor, JNJ-64619178, that prevents SNRPD3 methylation was cytotoxic in neuroblastoma cell lines with high SNRPD3 and MYCN expression. Overall, our findings demonstrate a selective relationship exhibited between MYCN and SNRPD3 and suggest that SNRPD3 plays a vital role in MYCN-driven tumorigenesis and could serve as a novel therapeutic target.
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Project description:The cooperation among the core regulatory circuitry transcription factors and MYCN on DNA binding [HAND2-MYCN-CRC-knockdown_ChIPseq]
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Project description:we find METTL3 associates with polyribosomes and promotes translation. METTL3 depletion inhibits translation, and both wild-type and catalytically inactive METTL3 promote translation when tethered to the 3' untranslated region (UTR) of a reporter mRNA. Mechanistically, METTL3 enhances mRNA translation through an interaction with the translation initiation machinery. m6A seq in A549 and H1299 cells, RNA seq in METTL3 knockdown cells
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Project description:To gain insight into possible processes that require m6A for their function, METTL3 was knocked down (KD) in HepG2 cells by siRNA transfections Differential expression analysis of METTL3 KD versus mock-transfected HepG2 cells, in 2 biological replicates
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