Longitudinal study of the human sperm methylome aging through whole-genome bisulfite sequencing
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE222340 | GEO | 2023/03/01
REPOSITORIES: GEO
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Project description:Paternal stress can induce long-lasting changes in germ cells potentially propagating heritable changes across generations. To date, no studies have investigated differences in transmission patterns between stress-resilient and -susceptible mice. We tested the hypothesis that transcriptional alterations in sperm during chronic social defeat stress (CSDS) transmit increased susceptibility to stress phenotypes to the next generation. We demonstrate differences in offspring from stressed fathers that depend upon paternal category (resilient vs susceptible) and offspring sex. Importantly, artificial insemination reveals that sperm mediates some of the behavioral phenotypes seen in offspring. Using RNA-sequencing we report substantial and distinct changes in the transcriptomic profiles of sperm following CSDS in susceptible vs resilient fathers, with alterations in long noncoding RNAs (lncRNAs) predominating especially in susceptibility. Correlation analysis revealed that these alterations were accompanied by a loss of regulation of protein-coding genes by lncRNAs in sperm of susceptible males. We also identify several co-expression gene modules that are enriched in differentially expressed genes in sperm from either resilient or susceptible fathers. Taken together, these studies advance our understanding of intergenerational epigenetic transmission of behavioral experience.
2024-05-20 | GSE174780 | GEO
Project description:Dietary habits and obesity in fathers imprint upon progeny through epigenetic signals carried by sperm RNA. By activating hypothalamic AgRP neurons in mice to mimic obesity's effects, we observed significant alterations in sperm tsRNAs, miRNAs, and rsRNAs. These changes, particularly in tsRNAs, mirror those seen with short-term high-fat diets, suggesting a shared upstream regulatory mechanism involving AgRP neurons that influence metabolic epigenetic inheritance.
2024-10-22 | GSE277621 | GEO
Project description:Advanced paternal age at fertilization has been suggested to be a risk factor for neurodevelopmental, psychiatric and other disorders in offspring. One emerging hypothesis suggests that altered offspring phenotype is linked with age-related accumulation of epigenetic changes in the sperm of fathers. Given that paternal age is increasing in the developed world, understanding aging-related epigenetic changes in sperm is needed as well as environmental factors that modify such changes. In this study, we characterize age-dependent changes in sperm DNA methylation profiles between young pubertal (postnatal day (PNDs) 65) and mature (PND120) Wistar rats. We also analyze these changes in rats exposed perinatally to 0.2 mg/kg of ubiquitous environmental xenobiotic 2,2’,4,4’-tetrabromodiphenyl ether (BDE-47). Reduced representation bisulfite sequencing (RRBS) libraries were prepared from caudal epididymal sperm DNA and differentially methylated regions (DMRs; ≥ 10x coverage depth, ≥ 3 CpGs per cluster, ≥ 5% methylation change, q < 0.05) were identified via MethPipe package. We identified 21 and 9 exposure-related DMRs in sperm collected on PND65 and PND120, respectively. Two DMRs overlapped between the two time-points. This is the first study to demonstrate that environmentally-relevant perinatal exposure to PBDE results in long-lasting changes in sperm DNA methylation. In control animals, 5,319 age-dependent DMRs were identified, with 99.3% DMRs hypermethylated in mature animals compared to young pubertal rats. These age-related DMRs were enriched for functional categories essential for embryonic development, such as pattern specification, forebrain and sensory organ development, and the Wnt pathway. In BDE-47 exposed rats, sperm DNA methylation was higher in young pubertal and lower in mature animals when compared to controls, which resulted in a significant attenuation in the number of age-dependent DMRs (N = 189) identified in the exposed group. In conclusion, our results indicate that the natural aging process has profound effects on sperm methylation levels and this effect may be modified by environmental exposures. Moreover, our results further support the role of sperm DNA methylation as a likely mechanism by which advanced paternal age is associated with adverse offspring health and development.
2019-07-17 | GSE134362 | GEO
Project description:5-methylcytosine is a major epigenetic modification sometimes called "the fifth nucleotide". However, our knowledge of how offspring inherit the DNA methylome from parents is limited. We generated nine single-base resolution DNA methylomes including zebrafish gametes and early embryos. The oocyte methylome is significantly hypo-methylated compared to sperm. Strikingly, the paternal DNA methylation pattern is maintained throughout early embryogenesis. The maternal DNA methylation pattern is maintained until the 16-cell stage. Then, the oocyte methylome is gradually discarded through cell division, and progressively reprogrammed to a pattern similar to that of the sperm methylome. The passive demethylation rate and the de novo methylation rate are similar in the maternal DNA. By the midblastula stage, the embryo?s methylome is virtually identical to the sperm methylome. Moreover, inheritance of the sperm methylome facilitates the epigenetic regulation of embryogenesis. Therefore, besides DNA sequences, sperm DNA methylome is also inherited in zebrafish early embryos. hMeDIP-seq is performed in sperm,2-cell,16-cell,1k-cell and a input control sample 4 new samples are added to GSE44075. RNA-seq is performed in sperm, egg,1k-cell, germring samples .hMeDIP-seq is performed in sperm,2-cell,16-cell,1k-cell and a input control sample 10 new samples are added to GSE44075. Bisulfite-seq is performed for nine samples : sperm, egg,16-cell,32-cell,64-cell,128-cell,1k-cell , Germring and testis. TAB-seq is performed for one sample , 32-cell.
2013-05-20 | E-GEOD-44075 | biostudies-arrayexpress
Project description:To achieve the extreme nuclear condensation necessary for sperm function, most histones are replaced with protamines during spermiogenesis in mammals. Mature sperm retain only a small fraction of nucleosomes, which are, in part, enriched on gene regulatory sequences, and recent findings suggest that these retained histones provide epigenetic information that regulates expression of a subset of genes involved in embryo development after fertilization. We addressed this tantalizing hypothesis by analyzing two mouse models exhibiting abnormal histone positioning in mature sperm due to impaired poly(ADP-ribose) (PAR) metabolism during spermiogenesis and identified altered sperm histone retention in specific gene loci genome-wide using MNase digestion-based enrichment of mononucleosomal DNA. We then set out to determine the extent to which expression of these genes was altered in embryos generated with these sperm. For control sperm, most genes showed some degree of histone association, unexpectedly suggesting that histone retention in sperm genes is not an all-or-none phenomenon and that a small number of histones may remain associated with genes throughout the genome. The amount of retained histones, however, was altered in many loci when PAR metabolism was impaired. To ascertain whether sperm histone association and embryonic gene expression are linked, the transcriptome of individual 2-cell embryos derived from such sperm was determined using microarrays and RNA sequencing. Strikingly, a moderate but statistically significant portion of the genes that were differentially expressed in these embryos also showed different histone retention in the corresponding gene loci in sperm of their fathers. These findings provide new evidence for the existence of a linkage between sperm histone retention and gene expression in the embryo. Seven WT (wild-type) samples of one 2-cell embryo each, all from fathers treated with saline (controls). Each group A, B, D consists of eggs fertilized by the same father (each sample is a single 2 cell embryo, 2CE). Ten samples of 2CE from fathers treated with PJ34 (PARP inhibitor) for 6 weeks, in the same setup (PJ-MTM11-1 to PJ34-MTM14-2, offspring from fathers MTM11, MTM13 or MTM14). All mice are wild-type, strain 129SVE (=129S6/SvEvTac, Taconic).
2014-08-30 | E-GEOD-56182 | biostudies-arrayexpress
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
Project description:The diet consumed by fathers prior to procreation impacts metabolic phenotypes in their offspring, but the mechanisms underlying such intergenerational information transfer remain obscure. Here, we carried out extensive analysis of cytosine methylation patterns in murine sperm, generating whole genome methylation maps for 4 pools of sperm samples and for 12 individual sperm samples, as well as 61 genome-scale reduced-representation bisulfite sequencing (RRBS) methylation maps, using samples obtained from male mice consuming various diets. We found that epivariation, either stochastic or due to unknown demographic or environmental factors, was a far stronger contributor to the sperm methylome than was the diet consumed. Variation in cytosine methylation was particularly dramatic over tandem repeat families, including ribosomal DNA (rDNA) repeats, and rDNA methylation levels were heritable from one generation to the next. However, rDNA methylation was strongly correlated with genetic variation in rDNA copy number, and analysis of hundreds of sperm samples revealed no consistent effect of diet on rDNA copy number or methylation level in sperm, indicating that paternal diet exerts an rDNA methylation-independent effect on offspring gene expression. These results reveal loci of genetic and epigenetic lability in the mammalian genome, but strongly argue against a direct mechanistic role for sperm cytosine methylation in dietary reprogramming of offspring metabolism.
2015-12-17 | GSE75323 | GEO
Project description:5-methylcytosine is a major epigenetic modification sometimes called "the fifth nucleotide". However, our knowledge of how offspring inherit the DNA methylome from parents is limited. We generated nine single-base resolution DNA methylomes including zebrafish gametes and early embryos. The oocyte methylome is significantly hypo-methylated compared to sperm. Strikingly, the paternal DNA methylation pattern is maintained throughout early embryogenesis. The maternal DNA methylation pattern is maintained until the 16-cell stage. Then, the oocyte methylome is gradually discarded through cell division, and progressively reprogrammed to a pattern similar to that of the sperm methylome. The passive demethylation rate and the de novo methylation rate are similar in the maternal DNA. By the midblastula stage, the embryo?s methylome is virtually identical to the sperm methylome. Moreover, inheritance of the sperm methylome facilitates the epigenetic regulation of embryogenesis. Therefore, besides DNA sequences, sperm DNA methylome is also inherited in zebrafish early embryos.
2013-05-20 | GSE44075 | GEO
Project description:Following their production in the testis, spermatozoa enter the epididymis to gain their motility and fertilizing abilities. This post-testicular maturation coincides with sperm epigenetic profile changes that influence the progeny outcome. While recent studies underscored the dynamics of small non-coding RNAs in the maturing spermatozoa, little is known regarding sperm methylation changes and their impact at the post-fertilization level. To map out the sperm methylome dynamics, we purified spermatozoa by FACS from the testis and the different epididymal segments (i.e. caput, corpus and cauda) of CAG/su9-DsRed2; Acr3-EGFP transgenic mice. Reduced-Representation Bisulfite Sequencing (RRBS-Seq) performed on DNA from these respective sperm populations indicated that high methylation changes were observed between spermatozoa from the caput vs. testis with 5546 entries meeting our threshold values (q value < 0.01, methylation difference above 25 %). Most of these changes were transitory during epididymal sperm maturation according to the low number of entries identified between spermatozoa from cauda vs. testis.
2022-03-10 | GSE191051 | GEO
Project description:We hypothesized that the availability of folate, a soluble B vitamin, would alter the levels of DNA methylation in spermatogenesis with consequences for the sperm epigenome and pregnancy outcomes. We fed male mice with either a folate-deficient or a folate-sufficient diet throughout life. Males fed the folate-deficient diet had offspring with increased birth defects, which included craniofacial and musculoskeletal malformations. These phenotypes corresponded to developmental genes with altered methylation in sperm. To determine if there was transmission of epigenetic effects from sires to offspring, global gene expression levels were assessed in placenta from 18.5 dpc fetuses sired by either a folate-sufficient or folate-deficient male. Gene expression was measured in placenta of 18.5 dpc fetuses sired by either a folate sufficient male (n=4 placentas from different litters and different fathers) or a folate deficient (FD) male (n=4 placentas from different litters and different fathers).
2013-11-06 | E-GEOD-51819 | biostudies-arrayexpress