DIPG-11. TRANSCRIPTIONAL REGULATION OF NEURAL PROGENITOR CELL FATE BY DLX HOMEOBOX GENES - RELEVANCE TO DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Bibliographic record
Abstract
DIPG is refractory to current therapies. The identification of histone H3.1/H3.3 K27M mutations in most DIPG has provided novel insights. DLX (distal-less) genes are expressed in the developing forebrain. The Dlx1/Dlx2 double knockout (DKO) mouse (dies at P0) has loss of tangential GABAergic interneuron migration to the neocortex. We have identified glutamic acid decarboxyase genes Gad1 and Gad2 as direct transcriptional targets of DLX1 and DLX2. In DIPG patients with H3.3 K27M there is decreased Dlx2 and increased expression of Myt1 (myelin transcription factor). We used bioinformatics and chromatin immunoprecipitation (ChIP) assays with embryonic ganglionic eminences to identify Olig2, Nkx2.2 and Myt1 promoter sequences as candidate DLX2 targets in vivo. DNA binding specificity was confirmed by electrophoretic mobility shift assays (EMSA). Co-expression of Dlx2 with luciferase reporter constructs of these ChIP-isolated promoter fragments of Olig2 and Nkx2.2 demonstrated repression of these gene targets in vitro. Assessment of target gene expression in the Dlx1/Dlx2 DKO forebrain by qPCR showed increased Olig2 and Nkx2.2 expression. Stable transfection of a murine HA-tagged DIPG cell line with Dlx2 increased expression of Gad1 and Gad2 and decreased expression of Olig2 and Nkx2.2. Of significance, using Western blotting we demonstrated decreased expression of H3.3 K27M and restoration of H3.3 K27 tri-methylation (me3). DLX transcription factors promote GABAergic interneuron differentiation and concomitant inhibition of oligodendroglial differentiation in neural progenitors by repression of a suite of genes including Olig2 and Nkx2.2. Restoration of H3 K27me3 expression in DIPG is a promising lead towards exploring differentiation as a therapeutic strategy for DIPG.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".