Mus musculus strain:BDF1
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REPOSITORIES: ENA
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Project description:In mammals, many germline genes are repressed by epigenetic mechanisms to prevent their illegitimate expression in embryonic and somatic cells. To advance our understanding of the complete mechanisms restricting the expression of germline genes in mammals, we analyzed the chromatin signature of germline genes and performed a genome-wide CRISPR-Cas9 knock-out screen for genes involved in germline gene repression using a reporter system in which GFP is under the control of the epigenetically repressed Dazl germline promoter in mouse embryonic stem cells (ESCs). We showed that the repression of germline genes mainly depends on the polycomb complex PRC1.6 and DNA methylation, which function additively in mouse ESCs. Furthermore, we identified and validated several novel genes involved in the repression of germline genes, and characterized three of them: Usp7, Shfm1 (also known as Sem1) and Erh. Inactivation of Usp7, Shfm1 or Erh led to the upregulation of germline genes, as well as retrotransposons for Shfm1, in mouse ESCs. Functionally, Usp7 acts at two levels: firstly it associates with PRC1.6 components and represses germline genes independently of DNA methylation, and secondly it facilitates DNA methylation deposition at germline genes for long term repression. In summary, our study provides a global view of the epigenetic mechanisms and novel factors required for silencing germline genes in embryonic cells.
2023-02-03 | PXD030666 | Pride
Project description:In the male mouse germline, PIWI-interacting RNAs (piRNAs), bound by the PIWI protein MIWI2 (PIWIL4), guide DNA methylation of young active transposons through SPOCD1. However, the underlying mechanisms of SPOCD1-mediated piRNA-directed transposon methylation and whether this pathway functions to protect the human germline remains unknown. We identified loss-of-function variants in human SPOCD1 that cause defective transposon silencing and male infertility. Through the analysis of one of these pathogenic alleles, we discovered that the uncharacterised protein C19ORF84 interacts with SPOCD1. DNMT3C, the DNA methyltransferase responsible for transposon methylation, associates with SPOCD1 and C19ORF84 in foetal gonocytes. Furthermore, C19ORF84 is essential for piRNA-directed DNA methylation and male mouse fertility. Finally, C19ORF84 mediates the in vivo association of SPOCD1 with the de novo methylation machinery. In summary, we have discovered a conserved role for the human piRNA pathway in transposon silencing and C19ORF84, an uncharacterised protein essential for orchestrating piRNA-directed DNA methylation.
2024-02-14 | PXD047331 | Pride
Project description:DNA methylation erasure is required for mammalian primordial germ cell reprogramming. TET enzymes iteratively oxidize 5-methylcytosine to generate 5-hyroxymethylcytosine (5hmC), 5-formylcytosine, and 5-carboxycytosine to facilitate active genome demethylation. Whether these bases are required to promote replication-coupled dilution or activate base excision repair during germline reprogramming remains unresolved due to the lack of genetic models that decouple TET1 activities. Here, we generated two mouse lines expressing catalytically inactive TET1 (Tet1-HxD) and TET1 that stalls at 5hmC (Tet1-V). This experiment was done to conduct genome wide DNA methylation profiling of catalytically inactive Tet1HxD/HxD sperm, 5hmC stalling Tet1V/V sperm, KO Tet1-/- sperm, and WT sperm. Sperm samples were collected from adult males (>10 week).
2024-02-27 | GSE249772 | GEO
Project description:DNA methylation erasure is required for mammalian primordial germ cell reprogramming. TET enzymes iteratively oxidize 5-methylcytosine to generate 5-hyroxymethylcytosine (5hmC), 5-formylcytosine, and 5-carboxycytosine to facilitate active genome demethylation. Whether these bases are required to promote replication-coupled dilution or activate base excision repair during germline reprogramming remains unresolved due to the lack of genetic models that decouple TET1 activities. Here, we generated two mouse lines expressing catalytically inactive TET1 (Tet1-HxD) and TET1 that stalls at 5hmC (Tet1-V). This experiment was done to conduct genome wide DNA methylation profiling of catalytically inactive Tet1HxD/HxD sperm, 5hmC stalling Tet1V/V sperm, KO Tet1-/- sperm, and WT sperm. Sperm samples were collected from adult males (>10 week).
2024-02-27 | GSE224349 | GEO
Project description:Testicular toxicity is one of the frequent adverse effects of cancer chemotherapy and the problem is that there is no effective biomarker. To find effective biomarkers, we focused on epigenetic mechanisms of male germline. Therefore, our study investigated the DNA methylation status of male germline under the testicular toxicity induced by doxorubicin(DXR), a widely used anticancer agent. We established mouse models of initial stage of testicular toxicity and testicular pre-toxicity by administrating 0.2 mg/kg and 0.02 mg/kg of DXR twice a week for 5 weeks. Western blotting analysis revealed the protein expression levels of DNA methyltransferases DNMT3a and DNMT3b were decreased in both the DXR administration groups. Consistently, comprehensive DNA methylation analysis of sperm DNA using MBD-seq revealed that the majority of methylation changes induced by DXR administration were hypomethylation. This study showed the possibility of early diagnosis of testicular toxicity by examining DNA methylation status of sperm.
2019-02-04 | GSE110227 | GEO
Project description:DNA methylation erasure is required for mammalian primordial germ cell reprogramming. TET enzymes iteratively oxidize 5-methylcytosine to generate 5-hyroxymethylcytosine (5hmC), 5-formylcytosine, and 5-carboxycytosine to facilitate active genome demethylation. Whether these bases are required to promote replication-coupled dilution or activate base excision repair during germline reprogramming remains unresolved due to the lack of genetic models that decouple TET1 activities. Here, we generated two mouse lines expressing catalytically inactive TET1 (Tet1-HxD) and TET1 that stalls at 5hmC (Tet1-V). This experiment was done to conduct genome wide DNA methylation profiling of catalytically inactive Tet1HxD/HxD sperm, 5hmC stalling Tet1V/V sperm, KO Tet1-/- sperm, and WT sperm. Sperm samples were collected from adult males (>10 week). E17.5 WT prospermatogonia were collected using FACS of Oct4-GFP cells and CUT&RUN for H3K4me3 and IgG were done on 130,000 cells.
2024-02-27 | GSE224458 | GEO
Project description:There is a growing body of evidence that inadequate maternal nutrition during gestation can have immediate and life-long effects on offspring. However, little is known about the reproductive effects of maternal gestational nutrition in offspring males. Here, using a sheep model of poor maternal nutrition (restricted- or over-feeding) during gestation, we found that poor maternal gestational nutrition does not affect semen characteristics (i.e. volume, sperm concentration, pH, sperm motility, sperm morphology) and scrotal circumference in offspring. However, by evaluating associations between poor maternal gestational nutrition and altered small non-cording RNAs (sncRNAs) and DNA methylation in offspring sperm, we demonstrated that poor maternal gestational nutrition alters sperm sncRNA composition and expression. Whole genome bisulfite sequencing further identified genomic regions with increased or decreased DNA methylation in sperm in response to poor maternal gestational nutrition. These findings imply that maternal diet-induced epigenetic errors can accumulate in sperm to worsen developmental outcomes of future generations.
2024-04-04 | GSE225985 | GEO
Project description:There is a growing body of evidence that inadequate maternal nutrition during gestation can have immediate and life-long effects on offspring. However, little is known about the reproductive effects of maternal gestational nutrition in offspring males. Here, using a sheep model of poor maternal nutrition (restricted- or over-feeding) during gestation, we found that poor maternal gestational nutrition does not affect semen characteristics (i.e. volume, sperm concentration, pH, sperm motility, sperm morphology) and scrotal circumference in offspring. However, by evaluating associations between poor maternal gestational nutrition and altered small non-cording RNAs (sncRNAs) and DNA methylation in offspring sperm, we demonstrated that poor maternal gestational nutrition alters sperm sncRNA composition and expression. Whole genome bisulfite sequencing further identified genomic regions with increased or decreased DNA methylation in sperm in response to poor maternal gestational nutrition. These findings imply that maternal diet-induced epigenetic errors can accumulate in sperm to worsen developmental outcomes of future generations.
2024-04-04 | GSE225924 | GEO
Project description:DNA methylation in sperm is among the most important factors shaping evolution of the mammalian genome. By directly altering germline mutation rates, the DNA methylation system has shaped the CpG landscape of mammalian genomes, resulting in the CpG island phenomenon. Yet little is known about how this system itself has co-evolved with its substrate during mammalian evolution. We analyzed full-genome single-CpG DNA methylation profiles in sperm from human, chimp, gorilla, rhesus, mouse, rat and dog. Our results point to an evolutionary expansion of the unmethylated portion of mammalian genomes. Within the mutually orthologous genome this trend is driven both by the birth of unmethylated regions and by widening of intervals that are unmethylated in ancestors. We find strikingly divergent global features in rodents. At the same time, we observe the evolutionary emergence of methylome features in mouse sperm bears association with similar pathways to those found in human. Together,these results revealed general principles in mammalian epigenome evolution.
2017-12-14 | GSE79566 | GEO
Project description:In mouse development, long-term silencing by CpG island DNA methylation is specifically targeted to germline genes, however the molecular mechanisms of this specificity remain unclear. Here we demonstrate that the transcription factor E2F6, a member of the polycomb repressive complex 1.6 (PRC1.6), is critical to target and initiate epigenetic silencing at germline genes in early embryogenesis. Genome-wide, E2F6 binds preferentially to CpG islands in embryonic cells. E2F6 cooperates with MGA to silence a subgroup of germline genes in mouse embryonic stem cells and in vivo, a function that critically depends on the E2F6 marked box domain. Inactivation of E2f6 leads to a failure to deposit CpG island DNA methylation at these genes during implantation. Furthermore, E2F6 is required to initiate epigenetic silencing in early embryonic cells but becomes dispensable for the maintenance in differentiated cells. Our findings elucidate the mechanisms of epigenetic targeting of germline genes and provide a paradigm for how transient repression signals by DNA-binding factors in early embryonic cells are translated into long term epigenetic silencing during mammalian development.
2021-04-22 | PXD023974 | Pride