Paternal diet induces transgenerational epigenetic inheritance of DNA methylation signatures and phenotypes in sheep model
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ABSTRACT:
PROVIDER: PRJNA817540 | ENA |
REPOSITORIES: ENA
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Project description:Parental environmental exposures can strongly influence descendant risks for adult disease. Metabolic disorders arise from the intersection of environmental and genetic risk factors, with epigenetic inheritance being at the center of the familial cycle of transgenerational disease. How paternal high-fat diet changes the sperm chromatin leading to the acquisition of metabolic disease in offspring remains controversial and ill-defined. Using a genetic model of epigenetic inheritance, we investigated the role of histone H3 lysine 4 methylation (H3K4me3) in the paternal transmission of metabolic dysfunction. We show that obesity-induced alterations in sperm H3K4me3 associated with offspring phenotypes and corresponded to embryonic and placental chromatin profiles and gene expression. Transgenerational susceptibility to metabolic disease was only observed when grandsires had a pre-existing genetic predisposition to metabolic dysfunction that was associated with enhanced alterations to sperm H3K4me3. This non-DNA based knowledge of inheritance has the potential to improve our understanding of how environment shapes heritability and may lead to novel routes for the prevention of disease.
2022-03-30 | GSE178096 | GEO
Project description:Transgenerational epigenetic inheritance (TEI) describes the transmission of gene-regulatory information across generations without altering DNA sequences. TEI allows priming of offspring towards changing environmental conditions and plays a role in the maintenance of gene silencing of selfish genetic elements like transposons. Small regulatory RNAs are well known to act in TEI, and can be transmitted via the male. Such inheritance via sperm requires dedicated mechanisms, as much of the cellular content is extruded during spermatogenesis. We identify a phase separation-based mechanism, which couples the paternal inheritance of a specific small RNA-bound silencing factor via S-palmitoylation to the transport of membranous organelles. Our findings uncover a thus far unknown paternal TEI mechanism, and describe a novel mode of transport of phase-separated condensates.
2021-03-26 | PXD019099 | Pride
Project description:We examined whether paternal diet from weaning to puberty induces sperm DNA methylation changes that can be transmitted to subsequent generations. Over 100 methylated cytosines environmentally altered in the F0 generation were inherited by the F1 and F2 generations. Furthermore, the F0 paternal diet was associated with growth and male fertility phenotypes in these generations. Differentially methylated genes also showed correlations with gene expression.
2023-01-04 | GSE198935 | GEO
Project description:Parental exposure to environmental stress can result in an increased diseases risk in the offspring. Although literature on maternal contribution to hereditary diseases are growing, the paternal contribution is frequently underrecognized. Since human studies reported that 80% of transmitted mutations arise in the paternal germline, it is crucial to understand the mechanism underlying the paternally inherited genome instability. Ionizing radiation (IR) is a major source of mutagenesis through inducing DNA double-strand breaks (DSBs). Here, we used sex-separated C. elegans mutants to investigate the paternal contribution to IR-induced transgenerational effects. Specifically, we found that paternal exposure to IR leads to a transgenerational embryonic lethality, and this effect is only observed when the radiation exposure occurred close to the time of fertilization. In the offspring of the irradiated males (F1 generation), we detected various genome instability phenotypes, including DNA fragmentation, chromosomal rearrangement, and aneuploidy. These phenotypes are attributed to the usage of two error-prone repair machinery, the polymerase-theta mediated end joining (TMEJ) and the non-homologous End Joining (NHEJ). Surprisingly, depletion of a human histone H1.0 ortholog, HIS-24, can significantly rescue this transgenerational embryonic lethality. Moreover, this rescue effect is associated with the downregulation of heterochromatin marker histone 3 lysine 9 di-methylation (H3K9me2), and the knocking-down of heterochromatin protein, HPL-1, could mimic the rescue effect of HIS-24 depletion. We also noticed that removal of the histone H1 and heterochromatin marker could activate the error-free repair machinery, Homologous Recombination repair (HR), thus improving the viability of the offspring carrying paternally inherited DNA damage. Altogether, our work sheds light on the importance of paternal radiation exposure on the health of offspring. In addition, our work establishes a previously unknown mechanism underlying the transgenerational genome instability and provides a potential therapeutic target for preventing the hereditary diseases caused by paternal radiation exposure.
2022-10-18 | PXD031873 | Pride
Project description:Genetic-epigenetic interactions in paternal transgenerational inheritance of metabolic disorders
| PRJNA737357 | ENA
Project description:Some epigenetic modifications are inherited from one generation to the next, providing a potential mechanism for the inheritance of environmentally acquired traits. Transgenerational inheritance of RNA interference phenotypes in C. elegans provides an excellent model to study this phenomenon, and whilst studies have implicated both chromatin modifications and small RNA pathways in heritable silencing their relative contributions remain unclear. Here we demonstrate that the histone methyltransferases SET-25 and SET-32 are required for the establishment of a transgenerational silencing signal, but not for long-term maintenance of this signal between subsequent generations suggesting that transgenerational epigenetic inheritance is a multi-step process, with distinct genetic requirements for establishment and maintenance of heritable silencing. Furthermore, small RNA sequencing reveals that the abundance of secondary siRNA (thought to be the effector molecules of heritable silencing) does not correlate with silencing phenotypes. Together, our results suggest that the current mechanistic models of epigenetic inheritance are incomplete.
2018-10-30 | PXD008754 | Pride
Project description:Transgenerational epigenetic inheritance (TEI) requires transmission of environmentally induced epigenetic changes and associated phenotypes to subsequent generations without continued exposure to the environmental factor that originated the change. TEI is well-established in plants and Caenorhabditis elegans; however, occurrence in mammals is debated and poorly understood. Here, we examined whether paternal diet from weaning to puberty-induced changes in sperm DNA methylation that were transmitted to subsequent generations. Over 100 methylated cytosines, environmentally altered in the F0 generation, were inherited by the F1 and F2 generations. Furthermore, the F0 paternal diet was associated with growth and male fertility phenotypes in subsequent generations. Differentially methylated cytosines were correlated with gene expression. Our results demonstrate that some sperm methylation sites may escape DNA methylation erasure and are transmitted to subsequent generations despite the 2 waves of epigenetic programming: in primordial germ cells and in embryos after fertilization. These results advance our understanding of the complex relationships between nature and nurture.
| S-EPMC9802161 | biostudies-literature
Project description:PRC2 mediates paternal epigenetic inheritance
| PRJNA282028 | ENA
Project description:Environmentally induced epigenetic transgenerational inheritance of adult onset disease involves a variety of phenotypic changes suggesting a general alteration in genome activity. Investigation of eleven different tissue transcriptomes in male and female F3 generation vinclozolin versus control lineage rats demonstrated all tissues examined had unique transgenerational transcriptomes. Common cellular pathways and processes were identified among the tissues. A bionetwork analysis identified gene modules with coordinated gene expression and each had unique gene networks regulating tissue specific gene expression and function. A large number of statistically significant over-represented clusters of differentially expressed genes were identified and termed M-bM-^@M-^\Epigenetic Control RegionsM-bM-^@M-^]. Combined observations demonstrate that all tissues derived from the epigenetically altered germ line develop transgenerational transcriptomes unique to the tissue, but common epigenetic control regions in the genome appear to in part coordinately regulate these tissue specific transcriptomes. This systems biology approach provides insight into the molecular mechanisms involved in the epigenetic transgenerational inheritance of a variety of adult onset disease phenotypes. We used microarrays to determine genes expressed differentially in rats 11 male or female smatic tissues -male heart, kidney, liver, testis, prostate, seminal vesicles; female heart, kidney, liver, ovary, uterus - due to Vinclozolin treatments of their grand-grandmothers. For each of 11 male or female smatic tissues, RNA samples from 2 treatment groups - control (Con) and vinclozolin (Vin) - were compared to each other. Each treatment groups contained 3 biological replica. RNA for each replica was pooled from 2 individual animals.
2012-06-30 | E-GEOD-35839 | biostudies-arrayexpress
Project description:Advancing the molecular knowledge surrounding fertility and inheritance has become critical given the halving of sperm counts in the last 40 years, and the rise in complex disease which cannot be explained by genetics alone. The connection between both these trends may lie in alterations to the sperm epigenome and occur through environmental exposures. Changes to the sperm epigenome are also associated with health risks across generations such as metabolic disorders and cancer. Thus it is imperative to identify the epigenetic modifications that escape reprogramming during spermatogenesis. Here, we aimed to identify the chromatin signature(s) associated with transgenerational phenotypes in our genetic mouse model of epigenetic inheritance that overexpresses the histone demethylase KDM1A in their germ cells. We used sperm-specific chromatin immunoprecipitation followed by in depth sequencing (ChIP-seq), and computational analysis to identify whether differential enrichment of histone H3 lysine 4 trimethylation (H3K4me3), and histone H3 lysine 27 trimethylation (H3K27me3) serve as mechanisms for transgenerational epigenetic inheritance through the paternal germline. Our analysis on the sperm of KDM1A transgenic males revealed specific changes in H3K4me3 enrichment that occurred independently from non-bivalent H3K4me3/H3K27me3 regions. Many regions with altered H3K4me3 enrichment in sperm were identified on the paternal allele of the pre-implantation embryo. These findings suggest that sperm H3K4me3 functions in the transmission of non-genetic phenotypes transgenerationally.
2020-10-15 | GSE145679 | GEO