DNMT1 Downregulation to Correct Genome-Wide Hypomethylation
Curated pathway from expert analysis
flowchart TD
A["DNMT1 Maintenance Methyltransferase<br/>PCNA-Dependent Replication"]
B["Genomic Stability<br/>Centromeric and Pericentromeric Methylation"]
C["DNA Damage Response<br/>Mismatch Repair and CpG Island Maintenance"]
D["Neuronal Epigenetic Memory<br/>Synaptic Gene Silencing"]
E["DNMT1 Deficiency<br/>Global Hypomethylation and Genomic Instability"]
F["DNMT1 Compensation<br/>Synaptic Resilience Gene Reactivation"]
A --> B
B --> C
C --> D
D --> E
F -.->|"counteracts"| E
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style D fill:#1b5e20,stroke:#81c784,color:#81c784
style E fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for DNMT1 yet. Search RCSB →
Median TPM across 13 brain regions for DNMT1 from GTEx v10.
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for DNMT1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF AD patients with high baseline DNMT1 expression (top quartile in cerebrospinal fluid mononuclear cells) receive 6-month treatment with DNMT1-lowering intervention (siRNA or small molecule), THEN CS | Cohort receiving DNMT1 modulation will show significant reduction in neuroinflammatory markers and stable or improved cognitive scores versus declining trajecto | — no observation — | pending | 0.40 |
| IF DNMT1 is downregulated (via CRISPRi or pharmacological inhibition) in iPSC-derived neurons from Alzheimer's disease patients for 14-21 days, THEN global DNA methylation levels will increase by ≥15% | Global DNA methylation levels in treated neurons will increase toward age-matched healthy control neuron values, with mean beta values increasing by ≥0.15 from | — no observation — | pending | 0.55 |