GADD45 promotes locus specific DNA demethylation and 2C cycling in embryonic stem cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA525097 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3922170.fastq.gz | Fastqsanger.gz | |||
| SRR3922180.fastq.gz | Fastqsanger.gz | |||
| SRR3922190.fastq.gz | Fastqsanger.gz | |||
| SRR3922200.fastq.gz | Fastqsanger.gz | |||
| SRR3922171.fastq.gz | Fastqsanger.gz |
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Project description:Mouse embryonic stem cell cultures contain a rare cell population of "2C-like" cells resembling 2-cell embryos, the key stage of zygotic genome activation (ZGA). Little is known about positive regulators of the 2C-like state and 2-cell stage embryos. We found that GADD45 (growth arrest and DNA damage 45) proteins, regulators of TET mediated DNA demethylation, promote both states. This SuperSeries is composed of the SubSeries listed below.
2019-05-31 | GSE127720 | GEO
Project description:Mouse embryonic stem cell (ESC) cultures contain a rare cell population of "2C-like" cells resembling two-cell embryos, the key stage of zygotic genome activation (ZGA). Little is known about positive regulators of the 2C-like state and two-cell stage embryos. Here we show that GADD45 (growth arrest and DNA damage 45) proteins, regulators of TET (TET methylcytosine dioxygenase)-mediated DNA demethylation, promote both states. Methylome analysis of Gadd45a,b,g triple-knockout (TKO) ESCs reveal locus-specific DNA hypermethylation of ∼7000 sites, which are enriched for enhancers and loci undergoing TET-TDG (thymine DNA glycosylase)-mediated demethylation. Gene expression is misregulated in TKOs, notably upon differentiation, and displays signatures of DNMT (DNA methyltransferase) and TET targets. TKOs manifest impaired transition into the 2C-like state and exhibit DNA hypermethylation and down-regulation of 2C-like state-specific genes. Gadd45a,b double-mutant mouse embryos display embryonic sublethality, deregulated ZGA gene expression, and developmental arrest. Our study reveals an unexpected role of GADD45 proteins in embryonic two-cell stage regulation.
| S-EPMC6601511 | biostudies-literature
Project description:Growth arrest and DNA-damage-inducible protein 45 (Gadd45) family members have been implicated in DNA demethylation in vertebrates. However, it remained unclear how they contribute to the demethylation process. Here, we demonstrate that Gadd45a promotes active DNA demethylation through thymine DNA glycosylase (TDG) which has recently been shown to excise 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) generated in Ten-eleven-translocation (Tet) -initiated oxidative demethylation. The connection of Gadd45a with oxidative demethylation is evidenced by the enhanced activation of a methylated reporter gene in HEK293T cells expressing Gadd45a in combination with catalytically active TDG and Tet. Gadd45a interacts with TDG physically and increases the removal of 5fC and 5caC from genomic and transfected plasmid DNA by TDG. Knockout of both Gadd45a and Gadd45b from mouse ES cells leads to hypermethylation of specific genomic loci most of which are also targets of TDG and show 5fC enrichment in TDG-deficient cells. These observations indicate that the demethylation effect of Gadd45a is mediated by TDG activity. This finding thus unites Gadd45a with the recently defined Tet-initiated demethylation pathway. The dataset includes RRBS anlysis of 2 WT ES cell samples and 2 Gadd45a/b DKO ES cell samples.
2015-05-07 | E-GEOD-62496 | biostudies-arrayexpress
Project description:Growth arrest and DNA-damage-inducible protein 45 (Gadd45) family members have been implicated in DNA demethylation in vertebrates. However, it remained unclear how they contribute to the demethylation process. Here, we demonstrate that Gadd45a promotes active DNA demethylation through thymine DNA glycosylase (TDG) which has recently been shown to excise 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) generated in Ten-eleven-translocation (Tet) -initiated oxidative demethylation. The connection of Gadd45a with oxidative demethylation is evidenced by the enhanced activation of a methylated reporter gene in HEK293T cells expressing Gadd45a in combination with catalytically active TDG and Tet. Gadd45a interacts with TDG physically and increases the removal of 5fC and 5caC from genomic and transfected plasmid DNA by TDG. Knockout of both Gadd45a and Gadd45b from mouse ES cells leads to hypermethylation of specific genomic loci most of which are also targets of TDG and show 5fC enrichment in TDG-deficient cells. These observations indicate that the demethylation effect of Gadd45a is mediated by TDG activity. This finding thus unites Gadd45a with the recently defined Tet-initiated demethylation pathway.
2015-05-07 | GSE62496 | GEO
Project description:We compared gene expression from 2C::tomato+/- ES cells from Kdm1a wt and mutant ES cultures 2C::tomato- samples 1, 5, 9 2C::tomato+ samples 2, 6, 10 We collecteded 3 replicates of RNA from 2C::tomato+ and - ES cells
2012-06-17 | E-GEOD-33763 | biostudies-arrayexpress
Project description:We compared gene expression from 2C::tomato+/- ES cells from Kdm1a wt and mutant ES cultures 2C::tomato- samples 1, 5, 9 2C::tomato+ samples 2, 6, 10
2012-06-18 | GSE33763 | GEO
Project description:We identified/quantified genes and repeat elements enriched within 2C::tomato+ cells vs. 2C::tomato - cells 2C::tomato + and - cells were collected by FACS for RNA-Seq analysis
2012-06-18 | E-GEOD-33920 | biostudies-arrayexpress
Project description:2C embryos were generated from Kdm1a FL/Fl Zp3Cre females mated to wild type males for RNA-seq analysis using the Nugen Ovation RNA-seq system V2 3 replicates of maternal Kdm1a mutant 2C embryos were collected for RNA-seq , compared to wt 2C embryos and wt oocyte samples from Macfarlan TS et al, Nature 2012 (GEO acession GSE33923)
2015-03-10 | E-GEOD-66547 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE33763: Expression data from 2C::tomato+ vs 2C::tomato - ES cells GSE33920: mRNA-Seq of 2C::tomato+ vs. - ES cells GSE33921: RNA-Seq from two-cell (2C) stage embryos GSE33922: RNA-Seq from wt oocytes GSE36896: RNA-Seq from wt and G9A knockout ES cells Refer to individual Series
2012-06-17 | E-GEOD-33923 | biostudies-arrayexpress
Project description:Mouse embryonic stem cells (ESCs) consist of a rare population of heterogeneous cells which express 2-cell-stage-specific transcripts and are referred to as 2-cell-like cells (2CLCs). Accumulating evidence has demonstrated that transcription factors and epigenetic modifications exert crucial functions in the transition of ESCs to 2CLCs. However, the roles of RNA modification in the regulation of 2C-like state remain elusive. Using Dux-induced 2CLCs system, we examine N6-methyladenosine (m6A) modification landscape in transcriptome-wide, and find that m6A is dynamically regulated during Dux-driven 2C-like reprogramming. Intriguingly, many of 2C-specific transcripts are highly methylated, including Dux and Zscan4 cluster genes. We further identify the m6A reader protein Ythdf2 as a critical regulator of 2C-like state. Depletion of Ythdf2 facilitates robust expressions of 2C transcripts and the transition of ESCs to 2CLCs. Mechanically, Ythdf2 binds to the Dux/Zscan4 transcripts and promotes their degradation through recruiting the key component of RNA deadenylase complex, Cnot1. Consistent with the phenotype of Ythdf2 deficiency, silencing of Cnot1 induces the 2C gene expressions and the transition of ESCs into the 2C-like state. Collectively, our findings reveal novel insights into the epitranscriptomic regulation of the 2C-like state in mouse ESCs.
2024-07-02 | GSE270881 | GEO