DIPG-14. PROTEOGENOMICS PROFILING REVEALS ENRICHED NON-HISTONE PROTEIN METHYLTRANSFERASES AS NEW THERAPEUTIC TARGETS IN DIPG
Bibliographic record
Abstract
Abstract Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumour arising in the brainstems of children. Despite advances in genomics and treatments, the survival rate remains zero, with a median of less than a year, making it the leading cause of death among children with brain tumours. A mutation in histone H3 protein (H3K27M) has been identified as a genetic initiation event and affects global K27 trimethylation on histone H3 proteins and DNA methylation in DIPG. The epigenetic changes caused by the H3K27M mutation suggest the existence of an H3K27M-specific transcriptome and proteome. To deepen our knowledge of DIPG, we conducted a proteogenomic analysis of DIPG tissues by using high-resolution mass spectrometry for comprehensive proteome profiling, including total proteome, phosphoproteome, and methylproteome. Integrating proteomics data with DNA methylation and transcriptomics (bulk RNAseq and single-cell RNAseq) provided new insights into DIPG tumorigenesis. Our multi-omics analyses reveal enriched translation machinery, negative regulation of apoptosis process, and non-histone protein methyltransferase proteins, suggesting their previously unknown roles in DIPG cell growth and survival. Furthermore, our findings indicate that DIPG tissues have lower global mean protein phosphorylation and higher global mean protein methylation compared to normal brains, implying that DIPG may use methyl-signaling rather than phospho-signaling for tumour growth. The translation elongation proteins EEF1A1 and EEF1A2 are the most highly methylated proteins in DIPG. Methylation modifications such as K55me2, K79me3, and K165me2 of EEF1A1 are significantly higher in DIPG tissues compared to normal brains. These enriched methylpeptides are substrates of the non-histone methyltransferases METTL13 and METTL21B, which are enriched in the multi-omics analysis. Knocking down these methyltransferases in DIPG cells significantly decreases their target protein methylation, reduces global protein synthesis, and inhibits cell growth in vitro. Thus, proteogenomic analysis of DIPG reveals tumour-enriched non-histone methyltransferases, METTL13 and METTL21B as new therapeutic targets.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".