Genetic-epigenetic interactions in paternal transgenerational inheritance of metabolic disorders
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ABSTRACT:
PROVIDER: PRJNA737357 | 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: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:Epigenetic information can be inherited through the mammalian germline, and represents a plausible transgenerational carrier of environmental information. To test whether transgenerational inheritance of environmental information occurs in mammals, we carried out an expression profiling screen for genes in mice that responded to paternal diet. As part of this analysis, we chracterise the changes in sperm cytosine methylation in response to different diets. Characterizing the RNA exression changes in livers of offspring mice in response to the paternal diet, comparing between low-protein diet and control-diet. Examination the effect of 3 different paternal diets, control diet, Caloric Restriction and low-protein diet, on sperm cytosine methylation.
2011-01-14 | E-GEOD-25898 | biostudies-arrayexpress
Project description:Epigenetic information can be inherited through the mammalian germline, and represents a plausible transgenerational carrier of environmental information. To test whether transgenerational inheritance of environmental information occurs in mammals, we carried out an expression profiling screen for genes in mice that responded to paternal diet. Characterizing the RNA exression changes in livers of offspring mice in response to the paternal diet, comparing between low-protein diet and control-diet. Examination of the effect of 2 different paternal diets, control diet and low-protein diet, on the mRNA expression in the liver of the offsprinngs. 26 samples: including Control diet vs. Low-protein (with dye swap), and Control diet vs. Low-protein after fasting the mice.
2011-01-14 | E-GEOD-25895 | biostudies-arrayexpress
Project description:Epigenetic information can be inherited through the mammalian germline, and represents a plausible transgenerational carrier of environmental information. To test whether transgenerational inheritance of environmental information occurs in mammals, we carried out an expression profiling screen for genes in mice that responded to paternal diet. Characterising the change in RNA expression in sperm in response to different paternal diets. Examination of the effect of different diets, control diet, low-protein diet and caloric-restriction diet, on the RNA expression in the sperm. 8 samples: 3 are control diets and 2 are low protein diets 1 caloric restriction diet, and 2 samples from Epidydimal tissue.
2011-01-14 | E-GEOD-25896 | biostudies-arrayexpress
Project description:Epigenetic information can be inherited through the mammalian germline, and represents a plausible transgenerational carrier of environmental information. To test whether transgenerational inheritance of environmental information occurs in mammals, we carried out an expression profiling screen for genes in mice that responded to paternal diet. Characterising the change in RNA expression in sperm in response to different paternal diets.
2011-01-14 | GSE25896 | GEO
Project description:Paternal chronic folate supplementation induced transgenerational inheritance of acquired developmental and metabolic changes in chickens
| PRJNA506246 | ENA
Project description:PRC2 mediated paternal epigenetic inheritance - E15.5
| PRJEB24910 | ENA
Project description:Epigenetic information can be inherited through the mammalian germline, and represents a plausible transgenerational carrier of environmental information. To test whether transgenerational inheritance of environmental information occurs in mammals, we carried out an expression profiling screen for genes in mice that responded to paternal diet. Characterizing the RNA exression changes in livers of offspring mice in response to the paternal diet, comparing between low-protein diet and control-diet.
2011-01-14 | GSE25895 | GEO