Sperm DNA Methylation Epimutation Biomarker for Paternal Offspring Autism Susceptibility
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA661265 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12581600_1.fastq.gz | Fastqsanger.gz | |||
| SRR12581600_2.fastq.gz | Fastqsanger.gz | |||
| SRR12581601_1.fastq.gz | Fastqsanger.gz | |||
| SRR12581601_2.fastq.gz | Fastqsanger.gz | |||
| SRR12581602_1.fastq.gz | Fastqsanger.gz |
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Project description:Autism spectrum disorder (ASD) has increased over ten-fold over the past several decades, and appears predominantly associated with paternal transmission. Although genetics is anticipated to be a component of ASD etiology, environmental epigenetics is now thought to be an important factor. Epigenetic alterations, such as DNA methylation have been correlated with ASD. The current study was designed to identify a DNA methylation signature in sperm as a potential biomarker to identify paternal offspring autism susceptibility. Sperm samples were obtained from fathers, many undergoing in vitro fertilization (IVF) procedures, that have children with or without autism, and the sperm then assessed for alterations in DNA methylation. Differential DNA methylation regions (DMRs) were identified in the sperm of fathers with autistic children in comparison to those without ASD children. An MeDIP-seq procedure was used to identify DMRs. The genomic features and genes associated with the DMRs were identified. The potential sperm DMR biomarker was validated with a blinded test set of individuals. Observations demonstrate a significant set of DMRs in sperm can potentially act as a biomarker for paternal offspring autism susceptibility.
2020-12-01 | GSE157417 | GEO
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Project description:Background: Epidemiological studies have reported an association between advanced paternal age at conception and an increased risk of neurodevelopmental disorders in offspring, such as autism spectrum disorder. Evidence suggests that DNA methylation alterations in sperm of older men may be transmitted to the feto-placental unit and associated with offspring brain development and behavioral differences later in childhood. Objective: We aimed to assess the association of advanced paternal age with DNA methylation alterations in the human placenta and compare the results to previous findings in sperm. Methods: For this study, 64 placenta samples from the 3D (Design, Develop, Discover) prospective birth cohort study were categorized based on paternal age at conception. DNA methylation of the placenta was interrogated using the Illumina 850K array. There were no differentially methylated sites found to be statistically significant after correction for multiple comparisons, therefore sites with significant nominal p-values <0.05 were assessed and used to define differentially methylated regions (DMRs) associated with genes. Results: Advanced paternal age was associated with DNA methylation alterations in the placenta at up to 688 genes, with a predominance of hypomethylation (65%), including at 8 imprinted loci. About 7% of genes with age-associated DNA methylation changes in placenta overlapped with genes previously reported to show altered DNA methylation in sperm of older men; seven genes common to placenta and sperm had previously been identified in association with susceptibility to autism spectrum disorder. Amongst loci most affected, we found evidence of sex-specific hypermethylation at genes linked to neurodevelopment (GRM7, EBF3, FOXG1). Conclusion: Our findings suggest that advanced paternal age at conception is associated with altered DNA methylation in the human placenta, including at genes tied to neurodevelopment. This study highlights the use of the placenta DNA methylome as a surrogate marker for the potential impact of advanced paternal age on the child.
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Project description:Sperm chromatin retains small amounts of histones, and the chromatin states of sperm mirror gene expression programs of the next generation. It remains largely unknown how paternal epigenetic information is transmitted through sperm chromatin. Here we developed a novel mouse model of paternal epigenetic inheritance in which deposition of Polycomb repressive complex 2 (PRC2) mediated-repressive H3K27me3 is attenuated in the paternal germline. By applying modified methods of assisted reproductive technology, we rescued infertility of mice absent of Polycomb protein SCML2, which is the regulator of germline gene expression through the establishment of H3K27me3 on bivalent promoters with other active marks H3K4me2/3. In F1 males of Scml2-knockout mice, which has wild-type genotype, gene expression is dysregulated in the male germline during spermiogenesis. These dysregulated genes are targets of SCML2-mediated H3K27me3 in mature sperm. Thus, SCML2 mediates intergenerational inheritance of paternal epigenetic information through the regulation of sperm chromatin.
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Project description:Obesity is a global epidemic influenced by stress-related experiences during development, which can program behavioral traits, with the amygdala playing a central role in stress regulation. These programmed effects may be inherited through epigenetic mechanisms. Here, we examined the impact of paternal early-life stress (ELS), alone or combined with a high-fat diet (HFD), on offspring behavior and gene regulation. Male Wistar rats underwent maternal separation to induce ELS, followed by elevated plus maze (EPM) testing and exposure to either HFD or standard chow. These males were bred with naïve females, and F1 offspring were raised under standard conditions. Amygdala tissue and sperm were collected; RNA from paternal and offspring amygdalae was deep-sequenced, and sperm DNA was analyzed using Reduced Representation Bisulfite Deep Sequencing (RRBS. Paternal exposure to ELS and HFD independently and jointly altered physiology and behavior in F1 female offspring. Offspring of ELS fathers showed increased exploratory behavior and mobility in the EPM, while; paternal HFD increased time spent in open arms. In the paternal amygdala, ELS and HFD induced distinct gene expression changes. Sperm methylation analysis revealed hundreds of differentially methylated genes, many overlapping with transcriptional changes in the F1 female amygdala, supporting a role for epigenetic inheritance. Overlapping expression patterns in F0 and F1 included genes involved in dopamine signaling and epigenetic regulation. Notably, the imprinted gene GRB10 showed increased promoter methylation in sperm and reduced expression in both paternal and offspring amygdala, validated by immunostaining. These findings suggest that paternal ELS and HFD shape offspring phenotype through heritable epigenetic modifications.
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Project description:Obesity is a global epidemic influenced by stress-related experiences during development, which can program behavioral traits, with the amygdala playing a central role in stress regulation. These programmed effects may be inherited through epigenetic mechanisms. Here, we examined the impact of paternal early-life stress (ELS), alone or combined with a high-fat diet (HFD), on offspring behavior and gene regulation. Male Wistar rats underwent maternal separation to induce ELS, followed by elevated plus maze (EPM) testing and exposure to either HFD or standard chow. These males were bred with naïve females, and F1 offspring were raised under standard conditions. Amygdala tissue and sperm were collected; RNA from paternal and offspring amygdalae was deep-sequenced, and sperm DNA was analyzed using Reduced Representation Bisulfite Deep Sequencing (RRBS. Paternal exposure to ELS and HFD independently and jointly altered physiology and behavior in F1 female offspring. Offspring of ELS fathers showed increased exploratory behavior and mobility in the EPM, while; paternal HFD increased time spent in open arms. In the paternal amygdala, ELS and HFD induced distinct gene expression changes. Sperm methylation analysis revealed hundreds of differentially methylated genes, many overlapping with transcriptional changes in the F1 female amygdala, supporting a role for epigenetic inheritance. Overlapping expression patterns in F0 and F1 included genes involved in dopamine signaling and epigenetic regulation. Notably, the imprinted gene GRB10 showed increased promoter methylation in sperm and reduced expression in both paternal and offspring amygdala, validated by immunostaining. These findings suggest that paternal ELS and HFD shape offspring phenotype through heritable epigenetic modifications.
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Project description:Obesity is a global epidemic influenced by stress-related experiences during development, which can program behavioral traits, with the amygdala playing a central role in stress regulation. These programmed effects may be inherited through epigenetic mechanisms. Here, we examined the impact of paternal early-life stress (ELS), alone or combined with a high-fat diet (HFD), on offspring behavior and gene regulation. Male Wistar rats underwent maternal separation to induce ELS, followed by elevated plus maze (EPM) testing and exposure to either HFD or standard chow. These males were bred with naïve females, and F1 offspring were raised under standard conditions. Amygdala tissue and sperm were collected; RNA from paternal and offspring amygdalae was deep-sequenced, and sperm DNA was analyzed using Reduced Representation Bisulfite Deep Sequencing (RRBS. Paternal exposure to ELS and HFD independently and jointly altered physiology and behavior in F1 female offspring. Offspring of ELS fathers showed increased exploratory behavior and mobility in the EPM, while; paternal HFD increased time spent in open arms. In the paternal amygdala, ELS and HFD induced distinct gene expression changes. Sperm methylation analysis revealed hundreds of differentially methylated genes, many overlapping with transcriptional changes in the F1 female amygdala, supporting a role for epigenetic inheritance. Overlapping expression patterns in F0 and F1 included genes involved in dopamine signaling and epigenetic regulation. Notably, the imprinted gene GRB10 showed increased promoter methylation in sperm and reduced expression in both paternal and offspring amygdala, validated by immunostaining. These findings suggest that paternal ELS and HFD shape offspring phenotype through heritable epigenetic modifications.
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