Epigenomic landscape of the developing human rhombic lip reveals gene regulatory network and non-coding loci of developmental, evolutionary, and disease relevance
Bibliographic record
Abstract
The cerebellar rhombic lip neural progenitor niche of the prenatal hindbrain is an anatomical structure critical for cerebellar glutamatergic neurogenesis. Humans have elaborated the rhombic lip niche to include a rhombic lip subventricular zone (RL-SVZ) not seen in mice or macaques. Although developmental disruptions of this progenitor zone can cause cerebellar growth abnormalities - from malformations to tumors - the gene regulatory networks underpinning this unique progenitor niche are unknown. Here we provide a predicted gene regulatory network for the human cerebellar rhombic lip, inferred from epigenomic maps of the developing human cerebellum. We generated DNA methylomes of neuroanatomically-dissected mid-gestation human rhombic lip ventricular zone and RL-SVZ (N=9 samples; 15-16 post conception weeks) using low-input Enzymatic MethylSeq. We also mapped histone modifications marking active promoters and enhancers in the whole mid-gestation human fetal cerebellum (N=6 samples; 14 and 18 post-conception weeks). Integrating these data, we identified 9,855 differentially-methylated regions (DMR) which converge on binding sites of over three hundred transcription factors, including master regulators of rhombic lip neurogenesis, ATOH1, NEUROD1, and NEUROD2. DMRs hypomethylated in the RL-SVZ are enriched in active enhancers and in human accelerated regions, and are depleted in active promoters. We inferred 81,844 transcription factor-enhancer-gene links, covering 41 transcription factors active in the rhombic lip, and 4,610 target genes that include drivers of cerebellar neurogenesis and pediatric hindbrain cancer. Twenty-five DMRs overlap human accelerated regions located near genes associated with intellectual disability, autism spectrum disorders, and neurological deficits. DMRs are also statistically enriched in copy number aberrations in medulloblastoma, a malignant pediatric hindbrain cancer with subtypes hypothesized to originate in the rhombic lip. Close to one-quarter of the DMRs overlap known copy number aberrations in medulloblastoma, nominating potential enhancer and promoter elements impacted by these genomic aberrations. Collectively, our data provide a rich resource to start decoding the functional impact of non-coding variation on gene regulation in the developing cerebellum and on genomic dysregulation in diseases of cerebellar growth.
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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".