The paternal sperm epigenome: implications for development and disease
Notice bibliographique
Résumé
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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».