FTDC1/2, oocyte-specific cofactors of DNMT1 required for epigenetic regulation and embryonic development
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ABSTRACT:
PROVIDER: PRJNA1031544 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26498650_1.fastq.gz | Fastqsanger.gz | |||
| SRR26498650_2.fastq.gz | Fastqsanger.gz | |||
| SRR26498651_1.fastq.gz | Fastqsanger.gz | |||
| SRR26498651_2.fastq.gz | Fastqsanger.gz | |||
| SRR26498652_1.fastq.gz | Fastqsanger.gz |
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Project description:FTDC1/2, oocyte-specific cofactors of DNMT1 required for epigenetic regulation and embryonic development (Bisulfite-Seq)
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Project description:In order to obtain genome-wide profiles, base-resolution methylomes of oocytes, 4-cells and blastocysts were generated using the bisulfite sequencing (BS-seq) method for few samples. We find that global loss of DNA methylation during preimplantation development in Ftdc1-/-and Ftdc2-/- mice. Such a loss of methylation upon Ftdc1 or Ftdc2 inactivation is truly global and occurs across all chromosomes and genomic features examined, such as exon, intron, transposon and etc. To refine the analysis, we identified 7,311 and 6,208 hypomethylated differentially methylated regions (hypo-DMRs) and no hypermethylated DMRs (hyper-DMRs) in Ftdc1- and Ftdc2-null blastocyst compared to WT, respectively. To test whether FTDC1/2 deficiency and the observed global hypomethylation have an impact on transcriptional activity, we conducted RNA-sequencing in WT and Ftdc1- or Ftdc2-null blastocysts. 1,886 and 1,073 differentially expressed genes were identified in Ftdc1-/-(up 945, down 941) and Ftdc2-/- embryos (up 945, down 941). Gene ontology (GO) analysis showed that these DEGs are primarily enriched in gastrulation, autophagy, adhesion, and immune system-related pathways. To assess the potential effects of FTDC1/2 deficiency on histone modifications, our genome-wide profiles of H3K9me3 in blastocysts revealed that FTDC1/2 depletion results in the massive loss of H3K9me3. In contrast, H3K9me3 was correspondingly reduced in those hypo-DMRs in Ftdc1-/- and Ftdc2-/- embryos.
2025-05-18 | GSE246099 | GEO
Project description:In order to obtain genome-wide profiles, base-resolution methylomes of oocytes, 4-cells and blastocysts were generated using the bisulfite sequencing (BS-seq) method for few samples. We find that global loss of DNA methylation during preimplantation development in Ftdc1-/-and Ftdc2-/- mice. Such a loss of methylation upon Ftdc1 or Ftdc2 inactivation is truly global and occurs across all chromosomes and genomic features examined, such as exon, intron, transposon and etc. To refine the analysis, we identified 7,311 and 6,208 hypomethylated differentially methylated regions (hypo-DMRs) and no hypermethylated DMRs (hyper-DMRs) in Ftdc1- and Ftdc2-null blastocyst compared to WT, respectively. To test whether FTDC1/2 deficiency and the observed global hypomethylation have an impact on transcriptional activity, we conducted RNA-sequencing in WT and Ftdc1- or Ftdc2-null blastocysts. 1,886 and 1,073 differentially expressed genes were identified in Ftdc1-/-(up 945, down 941) and Ftdc2-/- embryos (up 945, down 941). Gene ontology (GO) analysis showed that these DEGs are primarily enriched in gastrulation, autophagy, adhesion, and immune system-related pathways. To assess the potential effects of FTDC1/2 deficiency on histone modifications, our genome-wide profiles of H3K9me3 in blastocysts revealed that FTDC1/2 depletion results in the massive loss of H3K9me3. In contrast, H3K9me3 was correspondingly reduced in those hypo-DMRs in Ftdc1-/- and Ftdc2-/- embryos.
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Project description:DNA methylation is a key epigenetic modification involved in regulating gene expression and maintaining genomic integrity. Somatic patterns of DNA methylation are largely static, apart from focal dynamics at gene regulatory elements. To further advance our understanding of the role of DNA methylation in human development and disease, we inactivated all three catalytically active DNA methyltransferases in human embryonic stem cells (ESCs) using CRISPR/Cas9 genome editing. Disruption of DNMT3A or DNMT3B individually, as well as of both enzymes in tandem, creates viable, pluripotent cell lines with distinct effects on their DNA methylation landscape as assessed by whole-genome bisulfite sequencing. Surprisingly, in contrast to mouse, deletion of DNMT1 resulted in rapid cell death in human ESCs. To overcome the immediate lethality, we generated a doxycycline (DOX) responsive tTA-DNMT1* rescue line and readily obtained homozygous DNMT1 mutant lines. However, DOX-mediated repression of the exogenous DNMT1* initiates rapid, global loss of DNA methylation, followed by extensive cell death, demonstrating that DNA methylation is essential for human ESCs cultured in standard conditions. In summary, our data provide a comprehensive characterization of DNMT mutant ESCs, including single base genome-wide maps of their targets. RRBS methylation profiling of a time course of DNMT1* withdrawal in human ES cells
2015-03-30 | E-GEOD-63279 | biostudies-arrayexpress
Project description:Clinical studies have revealed an increased incidence of growth and genomic imprinting disorders in children conceived using Assisted Reproductive Technologies (ART), and aberrant DNA methylation has been implicated. We propose that compromised oocyte quality associated with female infertility may make embryos more susceptible to the induction of epigenetic defects by ART. DNA methylation patterns in the preimplantation embryo are dependent on the oocyte-specific DNA methyltransferase 1o (DNMT1o), levels of which are decreased in mature oocytes of aging females. Here, we assessed the effects of maternal deficiency in DNMT1o (Dnmt1∆1o/+) in combination with superovulation and embryo transfer on offspring DNA methylation and development. We demonstrated a significant increase in the rates of morphological abnormalities in offspring collected from Dnmt1∆1o/+ females only when combined with ART. Together, maternal oocyte Dnmt1o deficiency and ART resulted in an accentuation of placental imprinting defects and the induction of genome-wide DNA methylation alterations, which were exacerbated in the placenta compared to the embryo. Significant sex-specific trends were also apparent, with a preponderance of DNA hypomethylation in females. Among genic regions affected, a significant enrichment for neurodevelopmental pathways was observed. Taken together, our results demonstrate that oocyte DNMT1o-deficiency exacerbates genome-wide DNA methylation abnormalities induced by ARTs in a sex-specific manner and plays a role in mediating poor embryonic outcome.
2016-09-01 | GSE85200 | GEO
Project description:Unlike that of mammals, the total DNA methylome of many cold-blooded vertebrates is globally inherited from gametes to early embryos. In zebrafish, this is however accompanied by sweeping “dememorization” of enhancers prior to fertilization for sperm and just after fertilization for oocyte, as they undergo full methylation and are not demethylated again until phylotypic stage. The significance of both global methylome inheritance and enhancer dememorization in early embryos remains largely unknown. Adding to the puzzles, the zygotic mutant zebrafish of dnmt1, the major DNA methylation maintenance methyltransferase, surprisingly can develop to term. To solve the role of DNA methylation in early development, we generated zebrafish embryos derived from dnmt1-knocking down oocytes using a recently developed method OMIS (Oocyte Microinjection in situ), which successfully eliminated DNA methylation before zygotic genome activation. dnmt1-deficient embryos failed to initiate epiboly and died around gastrulation. This is in part caused by activation of immune response and p53-regulated apoptosis, likely triggered by the derepression of transposable elements. Single cell RNA-seq further revealed defective differentiation in these mutants. DNA methylation is also required for the establishment of repressive histone marks H3K27me3 and H2AK119ub. Strikingly, the loss of DNA methylation leads to extensive derepression of somatic genes and enhancers, which acquire ectopic H3K27ac, accessible chromatin, and H3K4me3. These somatic enhancers are preferentially CG-rich and are bound by CG-containing TFs. By contrast, embryonic enhancers are generally CG-poor, methylation-insensitive, and are bound by CG-less TFs. Hence, the global DNA methylome inheritance is essential for vertebrate early development, and enhancer dememorization resets an epigenetic gate that separates embryonic and somatic programs.
2021-12-29 | GSE175951 | GEO
Project description:Lung endoderm development occurs through a series of finely coordinated transcriptional processes that are regulated by epigenetic mechanisms. However, the role of DNA methylation in regulating lung endoderm development remains poorly understood. We demonstrate that DNA methyltransferase 1 (Dnmt1) is required for early branching morphogenesis of the lungs and for restraining epithelial fate specification. Loss of Dnmt1 leads to an early branching defect, a loss of proximal endodermal cell differentiation, and an expansion of the distal endoderm compartment. Dnmt1 deficiency also leads to precocious distal endodermal cell differentiation with premature expression of alveolar type 2 cell restricted genes. These data reveal an important requirement for Dnmt1 mediated DNA methylation in early lung development to promote proper branching morphogenesis, maintain proximal endodermal cell fate, and suppress premature activation of the distal epithelial fate.
2020-01-24 | GSE129177 | GEO
Project description:Genome wide DNA methylation profiling of mESCs and neurons overexpressing DNMT1 and DNMT1 Y495C mutant form. The Infinium Mouse methylation Beadchip was used to obtain DNA methylation profiles across approximately > 285k methylation sites in DNA samples of mESCs and neurons. Samples included wild-type cell line (R1) and transgenic cell lines (R1wtDnmt1 and R1Dnmt1Y495C).
2023-12-01 | GSE241544 | GEO
Project description:DNA methylation is a key epigenetic modification involved in regulating gene expression and maintaining genomic integrity. Somatic patterns of DNA methylation are largely static, apart from focal dynamics at gene regulatory elements. To further advance our understanding of the role of DNA methylation in human development and disease, we inactivated all three catalytically active DNA methyltransferases in human embryonic stem cells (ESCs) using CRISPR/Cas9 genome editing. Disruption of DNMT3A or DNMT3B individually, as well as of both enzymes in tandem, creates viable, pluripotent cell lines with distinct effects on their DNA methylation landscape as assessed by whole-genome bisulfite sequencing. Surprisingly, in contrast to mouse, deletion of DNMT1 resulted in rapid cell death in human ESCs. To overcome the immediate lethality, we generated a doxycycline (DOX) responsive tTA-DNMT1* rescue line and readily obtained homozygous DNMT1 mutant lines. However, DOX-mediated repression of the exogenous DNMT1* initiates rapid, global loss of DNA methylation, followed by extensive cell death, demonstrating that DNA methylation is essential for human ESCs cultured in standard conditions. In summary, our data provide a comprehensive characterization of DNMT mutant ESCs, including single base genome-wide maps of their targets.
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Project description:Identification of the all RNA species associated with DNMT1. Using a comparative genome-scale approach we identified and correlated the RNA species physically associated with DNMT1 and proximal to the annotated genes to the methylation status of the corresponding loci and expression levels of the respective genes. This comparative approach delineated the first -DNMT1 centered- 'epitranscriptome' map, a comprehensive map cross-referencing DNMT1-interacting transcripts to (i) DNA methylation and (ii) gene expression profile. Relationship between DNMT1-RNA interactions, DNA methylation and gene expression
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