Erasure of DNA methylation in rat fetal germ cells is sex-specific and sensitive to maternal high-fat diet.
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE245803 | GEO | 2024/08/20
REPOSITORIES: GEO
Similar Datasets
Project description:Background: DNA methylation (DNAme) erasure and reacquisition occurs during prenatal male germ cell development; some further remodelling takes place after birth during spermatogenesis. Environmental insults during germline epigenetic reprogramming may affect DNAme, presenting a potential mechanism for transmission of environmental exposures across multiple generations. Objectives: We investigated how germ cell DNAme is impacted by lifetime exposures to diets containing either low or high, clinically relevant, levels of the methyl donor folic acid and whether resulting DNAme alterations were inherited in germ cells of male offspring of subsequent generations. Materials and Methods: Female mice were placed on a 7-fold folic acid deficient (7FD) and 10- or 20-fold supplemented (10FS and 20FS) diets before and during pregnancy. Resulting F1 litters were weaned on the respective diets. F2 and F3 males received control diets. Genome-wide DNAme was assessed in F1 spermatogonia, and in F1, F2 and F3 sperm. Results: In F1 germ cells, a greater number of differentially methylated cytosines (DMCs) was observed in spermatogonia as compared with F1 sperm for all folic acid diets. DMCs were lower in number in F2 versus F1 sperm, while an unexpected increase was found in F3 sperm. DMCs were predominantly hypomethylated, with genes in neurodevelopmental pathways commonly affected in F1, F2 and F3 male germ cells. While no DMCs were found to be inherited inter- or transgenerationally, we observed over-representation of repetitive elements, particularly young LINEs. Discussion and Conclusion: These results suggest that the prenatal window is the time most susceptible to folate-induced alterations in sperm DNAme in male germ cells. Altered methylation of specific sites in F1 sperm was not present in later generations. However, the finding of hypomethylated young LINE1 elements in sperm from F1 to F3 males provides insight into potential mechanisms of epigenetic inheritance of the effects of folate deficiency and supplementation.
2023-02-27 | GSE208329 | GEO
Project description:Genome-wide DNA demethylation, including the erasure of genome imprints, in primordial germ cells (PGCs), is critical as a first step for creating the totipotent epigenome in the germ line. Here, we provide evidence that contrary to the prevailing model involving active DNA demethylation, imprint erasure in mouse PGCs occurs in a manner consistent with replication-coupled passive DNA demethylation: PGCs erase imprints during their rapid proliferation with little de novo as well as maintenance DNA methylation potential and no major chromatin alterations. Our findings necessitate the re-evaluation of and provide novel insights into the mechanism of genome-wide DNA demethylation in PGCs.
2013-03-04 | GSE40412 | GEO
Project description:Genome-wide DNA demethylation, including the erasure of genome imprints, in primordial germ cells (PGCs), is critical as a first step for creating the totipotent epigenome in the germ line. Here, we provide evidence that contrary to the prevailing model involving active DNA demethylation, imprint erasure in mouse PGCs occurs in a manner consistent with replication-coupled passive DNA demethylation: PGCs erase imprints during their rapid proliferation with little de novo as well as maintenance DNA methylation potential and no major chromatin alterations. Our findings necessitate the re-evaluation of and provide novel insights into the mechanism of genome-wide DNA demethylation in PGCs. We performed expression analysis of primordial germ cells (PGCs) at embryonic days 10.5-13.5. Because the number of PGCs available at these stages were low, cDNAs were amplified by the method that we previously published (Kurimoto et al. 2006, NAR 34: e42 (PMID 16547197)). To include analysis of PGC gene expression at E9.5, we re-normalized the data from our E9.5 PGC samples (GSM744103, GSM744104) from our previous publication (Hayashi et al., 2011, Cell 146: 519-32 (PMD 21820164)) together with the data from this submission.
2013-03-04 | E-GEOD-40412 | biostudies-arrayexpress
Project description:Epigenetic reprogramming including demethylation of DNA occurs in mammalian primordial germ cells (PGCs) and in early embryos, and is important for the erasure of imprints and epimutations, and the return to pluripotency. The extent of this reprogramming and its molecular mechanisms are poorly understood. We previously showed that the cytidine deaminases Aid and Apobec1 can deaminate 5-methylcytosine in vitro and in E coli, and in the mouse are expressed in tissues in which demethylation occurs. Here we profiled DNA methylation throughout the genome by unbiased bisulfite Next Generation Sequencing (BS-Seq) in wildtype and Aid deficient PGCs at E13.5. Wildtype PGCs revealed dramatic genome-wide erasure of methylation to a level below that of methylation deficient (Np95-/-) ES cells, with female PGCs being less methylated than male ones. By contrast, Aid deficient PGCs were up to three times more methylated than wildtype ones; this substantial difference occurred throughout the genome, with introns, intergenic regions and transposons being relatively more methylated than exons. Relative hypermethylation in Aid deficient PGCs was confirmed by analysis of individual loci in the genome. Our results reveal that erasure of DNA methylation in the germ line is a global process, hence limiting the potential for transgenerational epigenetic inheritance. Aid deficiency interferes with genome-wide erasure of DNA methylation patterns, suggesting that Aid has a critical function in epigenetic reprogramming and potentially in restricting the inheritance of epimutations in mammals. Comparison of methylation in wild-type and Aid deficient mouse tissues
2010-01-26 | E-GEOD-19960 | biostudies-arrayexpress
Project description:PURPOSE: To examine if a parental high fat diet (HFD) influences metabolic health in two generations of offspring, and alters the germ cell (GC) transcriptome. PROCEDURE: GC-eGFP Sprague Dawley rats were weaned onto HFD (45% fat) or Control Diet (CD; 10% fat). After metabolic testing, founders (F0) were bred with controls, establishing the F1 generation. Germ cells from F0 males were isolated and their RNA sequenced. F1 rats were bred with control rats at 17 weeks to generate F2 offspring. FINDINGS: HFD resulted in 9.7% and 14.7% increased weight in male and female F0 respectively. F1 offspring of HFD mothers were heavier than controls. F1 daughters of HFD-fed males were also heavier. F2 male offspring derived from HFD-fed maternal grandfathers were 7.2% heavier, and exhibited increases of 31% in adiposity, 97% in plasma leptin and 300% in luteinising hormone to testosterone ratio. HFD exposure did not alter the F0 GC transcriptome. CONTROLS: Matched CD was consumed by all animals not consuming the HFD. Animals were compared to a parallel cohort of CD rats. CONCLUSIONS: HFD consumption by maternal grandfathers results in a disrupted metabolic phenotype in grandsons. This effect is not mediated by alterations to the GC transcriptome.
2016-08-17 | GSE80721 | GEO
Project description:Epigenetic reprogramming including demethylation of DNA occurs in mammalian primordial germ cells (PGCs) and in early embryos, and is important for the erasure of imprints and epimutations, and the return to pluripotency. The extent of this reprogramming and its molecular mechanisms are poorly understood. We previously showed that the cytidine deaminases Aid and Apobec1 can deaminate 5-methylcytosine in vitro and in E coli, and in the mouse are expressed in tissues in which demethylation occurs. Here we profiled DNA methylation throughout the genome by unbiased bisulfite Next Generation Sequencing (BS-Seq) in wildtype and Aid deficient PGCs at E13.5. Wildtype PGCs revealed dramatic genome-wide erasure of methylation to a level below that of methylation deficient (Np95-/-) ES cells, with female PGCs being less methylated than male ones. By contrast, Aid deficient PGCs were up to three times more methylated than wildtype ones; this substantial difference occurred throughout the genome, with introns, intergenic regions and transposons being relatively more methylated than exons. Relative hypermethylation in Aid deficient PGCs was confirmed by analysis of individual loci in the genome. Our results reveal that erasure of DNA methylation in the germ line is a global process, hence limiting the potential for transgenerational epigenetic inheritance. Aid deficiency interferes with genome-wide erasure of DNA methylation patterns, suggesting that Aid has a critical function in epigenetic reprogramming and potentially in restricting the inheritance of epimutations in mammals.
2010-01-26 | GSE19960 | GEO
Project description:Genomic imprinting is an allele-specific gene expression system important for mammalian development and function. The molecular basis of genomic imprinting is allele-specific DNA methylation 2. While it is well known that the de novo DNA methyltransferases Dnmt3a/b are responsible for the establishment of genomic imprinting, how the methylation mark is erased during primordial germ cell (PGC) reprogramming remains a mystery. Here we report that Tet1 plays a critical role in the erasure of genomic imprinting. We show that despite their identical genotype, progenies derived from mating between Tet1-KO males and wild-type females exhibit a number of variable phenotypes including placental, fetal and postnatal growth defects, and early embryonic lethality. These defects are, at least in part, caused by the dysregulation of imprinted genes, such as Peg10 and Peg3, which exhibit aberrant hypermethylation in the paternal allele of differential methylated regions (DMRs). RNA-seq reveals extensive dysregulation of imprinted genes in the next generation due to paternal functional loss of Tet1. Genome-wide DNA methylation analysis of E13.5 PGCs and sperm derived from Tet1-KO mice reveals hypermethylation of DMRs of imprinted genes in sperm, which can be traced back to PGCs. Dynamics of methylation change in Tet1-affected sites suggested that Tet1 swipes remaining methylation including imprinted genes at late reprogramming stage. We also revealed that Tet1play a role in paternal imprinting erasure in females germline. Thus, our study establishes a critical function for Tet1 in the erasure of genomic imprinting. Genome-wide DNA methylation analysis of E13.5 PGCs from control and Tet1-KO mice
2013-12-02 | E-GEOD-49762 | biostudies-arrayexpress
Project description:Genomic imprinting is an allele-specific gene expression system important for mammalian development and function. The molecular basis of genomic imprinting is allele-specific DNA methylation 2. While it is well known that the de novo DNA methyltransferases Dnmt3a/b are responsible for the establishment of genomic imprinting, how the methylation mark is erased during primordial germ cell (PGC) reprogramming remains a mystery. Here we report that Tet1 plays a critical role in the erasure of genomic imprinting. We show that despite their identical genotype, progenies derived from mating between Tet1-KO males and wild-type females exhibit a number of variable phenotypes including placental, fetal and postnatal growth defects, and early embryonic lethality. These defects are, at least in part, caused by the dysregulation of imprinted genes, such as Peg10 and Peg3, which exhibit aberrant hypermethylation in the paternal allele of differential methylated regions (DMRs). RNA-seq reveals extensive dysregulation of imprinted genes in the next generation due to paternal functional loss of Tet1. Genome-wide DNA methylation analysis of E13.5 PGCs and sperm derived from Tet1-KO mice reveals hypermethylation of DMRs of imprinted genes in sperm, which can be traced back to PGCs. Dynamics of methylation change in Tet1-affected sites suggested that Tet1 swipes remaining methylation including imprinted genes at late reprogramming stage. We also revealed that Tet1play a role in paternal imprinting erasure in females germline. Thus, our study establishes a critical function for Tet1 in the erasure of genomic imprinting. Genome-wide DNA methylation analysis of sperm derived from control and Tet1-KO mice
2013-12-02 | E-GEOD-49763 | biostudies-arrayexpress
Project description:Genomic imprinting is an allele-specific gene expression system important for mammalian development and function. The molecular basis of genomic imprinting is allele-specific DNA methylation 2. While it is well known that the de novo DNA methyltransferases Dnmt3a/b are responsible for the establishment of genomic imprinting, how the methylation mark is erased during primordial germ cell (PGC) reprogramming remains a mystery. Here we report that Tet1 plays a critical role in the erasure of genomic imprinting. We show that despite their identical genotype, progenies derived from mating between Tet1-KO males and wild-type females exhibit a number of variable phenotypes including placental, fetal and postnatal growth defects, and early embryonic lethality. These defects are, at least in part, caused by the dysregulation of imprinted genes, such as Peg10 and Peg3, which exhibit aberrant hypermethylation in the paternal allele of differential methylated regions (DMRs). RNA-seq reveals extensive dysregulation of imprinted genes in the next generation due to paternal functional loss of Tet1. Genome-wide DNA methylation analysis of E13.5 PGCs and sperm derived from Tet1-KO mice reveals hypermethylation of DMRs of imprinted genes in sperm, which can be traced back to PGCs. Dynamics of methylation change in Tet1-affected sites suggested that Tet1 swipes remaining methylation including imprinted genes at late reprogramming stage. We also revealed that Tet1play a role in paternal imprinting erasure in females germline. Thus, our study establishes a critical function for Tet1 in the erasure of genomic imprinting. Gene expression analysis of E9.5 embryos
2013-12-02 | E-GEOD-49761 | biostudies-arrayexpress
Project description:Genomic imprinting is an allele-specific gene expression system important for mammalian development and function. The molecular basis of genomic imprinting is allele-specific DNA methylation 2. While it is well known that the de novo DNA methyltransferases Dnmt3a/b are responsible for the establishment of genomic imprinting, how the methylation mark is erased during primordial germ cell (PGC) reprogramming remains a mystery. Here we report that Tet1 plays a critical role in the erasure of genomic imprinting. We show that despite their identical genotype, progenies derived from mating between Tet1-KO males and wild-type females exhibit a number of variable phenotypes including placental, fetal and postnatal growth defects, and early embryonic lethality. These defects are, at least in part, caused by the dysregulation of imprinted genes, such as Peg10 and Peg3, which exhibit aberrant hypermethylation in the paternal allele of differential methylated regions (DMRs). RNA-seq reveals extensive dysregulation of imprinted genes in the next generation due to paternal functional loss of Tet1. Genome-wide DNA methylation analysis of E13.5 PGCs and sperm derived from Tet1-KO mice reveals hypermethylation of DMRs of imprinted genes in sperm, which can be traced back to PGCs. Dynamics of methylation change in Tet1-affected sites suggested that Tet1 swipes remaining methylation including imprinted genes at late reprogramming stage. We also revealed that Tet1play a role in paternal imprinting erasure in females germline. Thus, our study establishes a critical function for Tet1 in the erasure of genomic imprinting.
2013-12-02 | GSE49763 | GEO