DNA Methylation Defects in Prenatal and Postnatal Germ Cells of Dnmt3L Haploinsufficient Male Mice.
Bibliographic record
Abstract
The enzyme DNA methyltransferase 3-like (DNMT3L) is essential for the acquisition of DNA methylation patterns in germ cells as well as normal germ cell development and has been reported as the first paternal effect gene in mammals. Although Dnmt3L heterozygous males are fertile, they have abnormalities in X chromosome compaction, postmeiotic gene expression and sire an increased number of pups with XO monosomy. To examine the postulated epigenetic basis of the paternal effects, we examined DNA methylation acquisition at intergenic (non-CpG island, non-repeat) sites along chromosome 9 in male germ cells isolated during the prenatal and postnatal periods. At 16.5 dpc (days post coitum), 42% of intergenic loci examined were hypomethylated, by 20–30%, in Dnmt3L heterozygotes as compared to Dnmt3L wildtype mice. By day 1 after birth DNA methylation differences in spermatogonia between the two genotypes had resolved for 67% of the sites; in contrast, 33% of sites showed residual hypomethylation, in the range of 10%, associated with Dnmt3L haploinsufficiency. By postnatal days 4 and 6, germ cell DNA methylation levels were similar in the heterozygous and wildtype mice and remained similar later in spermatogenesis in spermatozoa. The findings suggest that germ cell DNA methylation differences between the genotypes resolve shortly after birth before the spermatogonia begin to divide. To confirm and extend these results, higher resolution studies using Reduced Representation Bisulphite Sequencing (RRBS) are being carried out to examine methylation differences at 3-5 million CpG sites across the genome. The DNA methylation defects described here in prenatal and early postnatal male germ cells of Dnmt3L heterozygous mice are the earliest epigenetic perturbation yet identified for a mammalian paternal effect gene and may influence downstream epigenetic and genetic events that lead to the previously observed abnormalities during spermatogenesis and paternal effects in the offspring. (Supported by CIHR).
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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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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".