Bibliographic record
Abstract
Despite the father transmitting half the heritable information to the embryo the focus on preconception health has largely been on the mother. New studies highlight the role of the father in disease transmission via non-genetic inheritance, through epigenetic mechanisms. Epigenetic mechanisms include, DNA methylation, post-translational modifications of histones and noncoding RNAs. Paternal effects have been linked to developmental abnormalities and complex diseases such as cancer, diabetes and obesity. Studies in humans and animals have linked epigenetic inheritance to the transmission of environmentally induced phenotypic traits from the father to the developing embryo and these have been associated with altered gene expression and developmental abnormalities in first and second offspring generationsThe genome in mature spermatozoa is packaged in a very unique manner. Whereas the majority of the genome is packaged by sperm-specific nucleoproteins, the protamines, regulatory regions of many genes retain nucleosomes. Moreover, such nucleosomes carry posttranslational modifications in a manner that is highly suggestive of a function in embryo development. In our previous study we show that paternal folate deficiency (FD) is associated with increased birth defects, minor alterations to DNA methylation in the sperm including at genes implicated in development and chronic disease (Lambrot et al ., 2013. Nat Commun ). We also showed folate deficiency altered global levels of histone methylation in sperm, suggesting their involvement in epigenetic inheritance. To address the role of modified histones in sperm for embryonic development we generated transgenic mice over-expressing the human histone demethylase LSD1/KDM1A. Offspring sired by such transgenic mice suffered from major developmental abnormalities and increased neonatal death. Remarkably, overexpression of KDM1A in heterozygote fathers affected wild type offspring as well, even for three following generations. ChIP-Seq studies of sperm of transgenic fathers revealed that H3 lysine 4 dimethylation levels were reduced at promoters of over 2300 genes, many of which serve important functions during embryonic development. In contrast, nucleosome occupancy levels were unaltered at such genes, indicating that KDM1A overexpression affects homeostasis of H3K4me2 during spermatogenesis. Together, our data from environmental exposures and transgenicsstrongly support the idea that disruption of sperm epigenome homeostasis is extremely detrimental for embryonic fitness of offspring. Our data reveals the potential of genetic mutations in chromatin modifiers and of environmental-induced alterations to the sperm epigenome as an underlying cause of birth defects and disease that may be traceable to the father.
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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 | 0.000 | 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) | 0.000 | 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".