Over-Expression of the Histone H3 Demethylase KDM1 (Lysine Specific Demethylase 1) in Growing Oocytes Compromises Offspring Development.
Bibliographic record
Abstract
The role of the oocyte epigenome in oogenesis and in embryo development is poorly understood. Previous studies have established that correct establishment of DNA methylation patterns in the oocyte is essential for subsequent embryo development, yet the significance of histone modifications in the oocyte and downstream effects on embryos and offspring are unknown. The histone demethylase KDM1 which removes mono- and di-methylation from lysine 4 and 9 of histone 3 (H3K4, H3K9), is highly expressed in mouse reproductive tissues. Our first objective was to establish the distribution of KDM1 in the ovary. By immunolocalization in mouse ovarian sections, high levels of KDM1 were detected in granulosa cells of all follicular stages and in growing oocytes in primordial to secondary follicles. KDM1 persisted in antral oocytes isolated by follicular puncture. Following positive localization of KDM1 to growing oocytes we aimed to determine the consequences for offspring following its over-expression in the oocyte. We chose the approach of over-expression versus ablation as we hypothesized that by over-expression of KDM1 in the growing oocyte the levels of histone H3K4 and K9 methylation would be altered, yet the oocyte still viable. By analysis of offspring at embryonic day 18.5 we determined the effects of the altered oocyte epigenome on reproductive outcomes. In comparison to control dams (n=12), transgenic females (n=12) that over-expressed KDM1 in the oocyte, had significantly increased pre-implantation loss. Examination of fetuses indicated that the frequency of developmental abnormalities was greater in litters sired by transgenics. Our results indicate that KDM1 serves an important function in regulating epigenetic programming in the oocyte and that its targets histone H3-K4 and K9 appear to be key regulators in embryo development. Ongoing studies are aimed at defining the genes specific changes in the epigenome of KDM1 over-expressing oocytes and to link these alterations to the phenotypes observed in the offspring from KDM1 dams. This research is funded by the CIHR the Reseau Quebecois en Reproduction (RQR-FQRNT) and the McGill Center for the Study of Reproduction
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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) | 0.000 | 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 teacher head, 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".