Decreased Expression of the Histone Methyltransferase SUV39H1 in AML Cells Reactivates Hypermethylated Tumor Suppressor p15INK4B in the Absence of Promoter Demethylation.
Bibliographic record
Abstract
Abstract Re-expression of hypermethylated tumor suppressor genes using epigenetic modifiers, such as DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, occurs by a mechanism whereby promoter demethylation is the dominant event. In support of this model, we found that the DNMT inhibitor 5-Aza-2-deoxycytidine (decitabine) induces expression of the tumor suppressor gene p15INK4B (p15) in AML cells with hypermethylated p15 promoters. Re-expression of p15 by decitabine is associated with decreases in p15 promoter methylation and histone H3 lysine 9 (H3K9) methylation and increases in H3K9 acetylation. DNA methylation is linked to H3K9 methylation through the DNA methyl binding protein MeCP2, which associates with DNMTs and H3K9 methyltransferases. Using chromatin immunoprecipitaton (ChIP) assays, we confirmed that MeCP2, DNMT1 and the H3K9 methylatransferase SUV39H1 interact with the methylated p15 promoter and that this interaction is reduced by decitabine. To determine whether promoter demethylation is also dominant to H3K9 demethylation, we monitored p15 re-expression in the presence of SUV39H1 shRNA alone and in combination with decitabine. SUV39H1 shRNA induces p15 expression and H3K9 demethylation, however it does not affect p15 promoter methylation. These results are in contrast to the HDAC inhibitor trichostatin A (TSA), which cannot induce p15 re-expression. SUV39H1 shRNA induced p15 expression and H3K9 demethylation are also enhanced by co-treatment with decitabine or TSA. Surprisingly, co-treatment with decitabine and SUV39H1 shRNA partially reverses decitabine induced promoter demethylation. Using ChIP assays we show that SUV39H1 shRNA increases the amount of the histone H3K9 dimethytransferase G9a and DNMT1 associated with the p15 promoter. Increased levels of G9a at the p15 promoter would enhance promoter methylation since G9a stimulates DNMT1 activity. Our results demonstrate that hypermethylated p15 can be reactivated in AML cells by an initial event that involves H3K9 demethylation. In addition, we found that the SUV39H1 inhibitor chaetocin induces p15 in AML cells with hypermethylated p15 promoters. Therefore, H3K9 methylatransferases represent novel therapeutic targets for developing inhibitors to reactivate the expression of hypermethylated genes.
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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".