Abstract 2983: Gene resilencing following decitabine therapy is initiated by nucleosome reoccupancy and is related to CpG island shore methylation.
Bibliographic record
Abstract
Abstract Decitabine is a front line therapy for myelogenous leukaemias and is in clinical trials for various solid tumour types. This DNA demethylating agent reactivates genes silenced by promoter hypermethylation in cancer. However upon drug withdrawal reexpressed genes undergo remethylation (resilencing) which may underlie drug resistance and presents a barrier to effective therapy. We aimed to define the ordered sequence of epigenetic events associated with resilencing. Using biallelically methylated MLH1 as a model gene, we profiled epigenetic changes at the MLH1 promoter associated with reexpression and resilencing in a colorectal cancer cell line before, during and after Decitabine treatment. In contrast to the closed chromatin structure observed before treatment, Decitabine induced increased MLH1 expression and 54% decreased promoter methylation. We show that gene resilencing, which occurs 6-8 days following removal of therapy, is not due to promoter remethylation but is initiated by reoccupancy of nucleosomes to demethylated promoter alleles. Furthermore, long-term monitoring of cells following treatment showed MLH1 expression never reverts to pretreatment levels with low-level expression and demethylated promoter alleles persisting up to 118 days after withdrawal of Decitabine. Genome-wide methylation profiling was used to categorise promoter CpG Islands (CGI) based on their degree of demethylation after treatment. This revealed that CGIs with persistence of demethylated promoter alleles after long-term recovery (n=108) showed significantly lower levels of CGI shore methylation (p=0.0231). Our findings suggest a role for shore methylation in susceptibility to CGI remethylation and that therapeutic targeting of nucleosome assembly may provide a novel strategy to prevent gene resilencing. Citation Format: Vibha Patil, Mathew A. Sloane, Jason Wh Wong, Jia Liu, Robyn L. Ward, Luke B. Hesson. Gene resilencing following decitabine therapy is initiated by nucleosome reoccupancy and is related to CpG island shore methylation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2983. doi:10.1158/1538-7445.AM2013-2983
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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) | 0.003 | 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".