The acquisition, dynamics, and perturbation of DNA methylation in the prenatal and early postnatal male germline
Bibliographic record
Abstract
DNA methylation is an epigenetic modification that is essential for germline and embryo development. DNA methylation establishment occurs in the germline in a gender and site specific manner through the action of DNA cytosine-5-methyltransferase (DNMT) enzymes. Spermatozoa have been shown to have a unique configuration of DNA methylation as compared to somatic cells. Germline DNA methylation may also depend on the availability of methyl donors provided by the folate pathway through the action of 5,10-methylenetetrahydrofolate reductase (MTHFR). Absence of MTHFR has been associated with methylation loss in mature sperm as well as decreased male fertility. This thesis presents new data exploring the dynamics of DNA methylation at nonpromoter intergenic sites during the perinatal period in normal conditions and in the setting of perturbed expression of Dnmt3L and Mthfr. The key phase of DNA methylation acquisition in male germ cells was determined to occur during prenatal development of the germline suggesting that DNA methylation may be particularly vulnerable to in utero insults. DNA methylation acquisition was found to be a dynamic process at individual sites including loci that demonstrated incomplete erasure suggesting a potential for transgenerational inheritance of DNA methylation errors. Perturbation of the expression of Dnmt3L, a DNMT with no endogenous methylation activity, revealed that it may be responsible for not only directing DNA methylation to specific loci but also for controlling the timing of DNA methylation acquisition. Spermatogonial stem cell (SSC) cultures were developed as a model for examining DNA methylation in the male germline. While DNA methylation was stable in normal culture conditions, it could be perturbed by haploinsufficiency of either Dnmt3L or Mthfr. Further modification of culture conditions through changes of methionine concentration in Mthfr+/- SSC cultures resulted in increased variability of DNA methylation indicating a generalized effect of MTHFR on DNA methylation and possibly its interaction with other methyl group dependent processes such as histone methylation. This thesis presents a number of novel findings that begin to unravel the mechanisms of DNA methylation and epigenetic modification of the male germline.
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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".