BI-03 * DLX HOMEOBOX GENES REGULATE NEURONAL VS OLIGODENDROGLIAL CELL FATE DECISIONS: POTENTIAL RELEVANCE TO PEDIATRIC GLIONEURONAL TUMORS AND HIGH GRADE GLIOMAS
Bibliographic record
Abstract
BACKGROUND: Pediatric high grade gliomas (pHGG) are localized to different neuroanatomic compartments with significant differences in their gene expression profiles. In Histone H3.3 G34V/R mutants, DLX2 homeobox gene expression is increased with a corresponding decrease in myelin transcription factor (MYT1) expression. DLX genes are necessary for tangential migration and differentiation of inhibitory interneurons during CNS development. Neural progenitors derived from DLX1/DLX2 double knockout (DKO) mice transplanted into a wild-type forebrain differentiate into oligodendrocytes, providing support for the DLX homeobox genes in neuronal-glial cell fate decisions. METHODS: Chromatin immunoprecipitation (ChIP) assays using a DLX2 antibody were followed by qPCR. ChIP-reChIP assays were performed using antibodies that recognize specific histone modifications. Electrophoretic mobility shift assays (EMSA) were performed using recombinant DLX2 protein and oligonucleotide probes from ChIP-specified promoter regions. Reporter gene assays provided functional assessment of protein-DNA interactions in vitro. Target gene expression was assessed comparing wild-type (WT) and DLX1/DLX2 DKO tissues. RESULTS: Homeodomain binding sites were localized to the promoters of Olig2, Myt1, Nkx2.2 and others in silico. ChIP assays confirmed promoter occupancy by DLX2. ChIPseq experiments are underway. EMSA studies demonstrated specific DLX2-promoter complexes. Luciferase assays showed repression of Olig2 and Nkx2.2 reporter gene expression, consistent with co-occupancy of H3K27me3 in WT and increased target gene expression in DLX1/DLX2 DKO embryonic tissues. We also demonstrated DLX2 expression in a cohort of gangliogliomas. CONCLUSIONS: Our results support a role for DLX transcription factors in controlling neural progenitor specification by activating GABAergic and inhibiting oligodendroglial cell fates through transcriptional repression of a suite of genes required for oligodendrocyte differentiation. Understanding how pHGG and glioneuronal tumors co-opt these neurodevelopmental programs will lead to novel pharmacologic approaches that promote glioma differentiation.
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
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".