Mutated KLF4(K409Q) in meningioma binds STRs and activates FGF3 gene expression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA848234 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19631823_1.fastq.gz | Fastqsanger.gz | |||
| SRR19631823_2.fastq.gz | Fastqsanger.gz | |||
| SRR19631824_1.fastq.gz | Fastqsanger.gz | |||
| SRR19631824_2.fastq.gz | Fastqsanger.gz | |||
| SRR19631825_1.fastq.gz | Fastqsanger.gz |
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Project description:Krüppel-like factor 4 (KLF4) is a transcription factor that has been proven necessary for both induction and maintenance of pluripotency and self-renewal. Whole-genome sequencing defined a unique mutation in KLF4 (KLF4K409Q) in human meningiomas. However, the molecular mechanism of this tumor-specific KLF4 mutation is unknown. Using genome-wide high-throughput and focused quantitative transcriptional approaches in human cell lines, primary meningeal cells, and meningioma tumor tissue, we found that a change in the evolutionarily conserved DNA-binding domain of KLF4 alters its DNA recognition preference, resulting in a shift in downstream transcriptional activity. In the KLF4K409Q-specific targets, the normally silent fibroblast growth factor 3 (FGF3) is activated. We demonstrated a neomorphic function of KLF4K409Q in stimulating FGF3 transcription through binding to its promoter and in using short tandem repeats (STRs) located within the locus as enhancers.
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Project description:Meningiomas are the most common primary brain tumors, where complete surgical resection is often challenging giving rise to recurrence. Mutations of the E3 ubiquitin ligase TRAF7 are found in one-fourth of meningioma patients and typically co-occur with mutations in either KLF4, AKT1, or PI3KCA. By creating an in vitro meningioma model derived from primary meningeal cells, we elucidated the cooperative interactions that conspire meningioma development. A multi-omics framework on meningeal cells revealed TRAF7-mediated rewiring of the proteome with the majority of protein expression being post‐transcriptionally‐regulated. Integrating TRAF7-driven ubiquitinome and proteome alterations and TRAF7 interactome highlight the role of TRAF7 in posttranslational regulation of the cytoskeleton organization. TRAF7 controls actin dynamics by acting as a proteostatic regulator of the RAS-related small GTPases. TRAF7 loss-of-function diminishes ubiquitination of RAS and CDC42, leading to the activation of the PAK and MAPK signaling pathways. Up-regulation of CDC42 signaling promotes anchorage-independent growth of meningeal cells. On the other hand, the RAS/MAPK pathway triggers the tumor suppressive activity of KLF4 that inhibits meningeal cell growth due to the activation of the Semaphorin pathway. Simultaneous loss of KLF4 and TRAF7 function enhances tumorigenic transformation of meningeal cells, functionally confirming their roles in meningioma development.
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