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Polycomb PRC2 antagonizes de novo DNA methylation at the maternal Gtl2-Rian-Mirg locus

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE58414 | GEO | 2015/07/15

SECONDARY ACCESSION(S): PRJNA255384

REPOSITORIES: GEO

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Polycomb PRC2 antagonizes de novo DNA methylation at the maternal Gtl2-Rian-Mirg locus [Affymetrix Expression]

Project description:Wild-type mouse embryonic stem cells are compared with mutants for components of PRC2 including Ezh2-/-, Eed-/-, and Jarid2-/- cells. Gene expression microarrays were used to compare the expression for these. This experiment compares wild-type gene expression with mutants for different PRC2 components, including Ezh2-/-, Eee-/- and Jarid2-/- with two replicates for each using Affymetrix Gene Expression Arrays.

2015-07-15 | E-GEOD-59464 | biostudies-arrayexpress

Polycomb PRC2 antagonizes de novo DNA methylation at the maternal Gtl2-Rian-Mirg locus [Affymetrix Expression]

2015-07-15 | GSE59464 | GEO

Polycomb PRC2 antagonizes de novo DNA methylation at the maternal Gtl2-Rian-Mirg locus [Next-Gen Sequence Data]

Project description:Wild-type mouse embryonic stem cells are compared with mutants for components of PRC2 including Ezh2-/-, Eed-/-, and Jarid2-/- cells. Chromatin modifications, Gene expression, Pol-II, small-RNA sequencing, and DNA methylation are compared for both cell types. To study genomic and epigentic control of PRC2 in mESCs, we designed gene expression analysis (RNA-Seq and small RNA-Seq), combining with ChIP-Seq analysis of several factors and histone marks from wild-type and distinct PRC2 mutants including wild-type, Ezh2-/-, Eed-/-, and Jarid2-/-.

2015-07-15 | E-GEOD-59463 | biostudies-arrayexpress

Polycomb PRC2 antagonizes de novo DNA methylation at the maternal Gtl2-Rian-Mirg locus [Next-Gen Sequence Data]

2015-07-15 | GSE59463 | GEO

PRC2 Is Required to Maintain Expression of the Maternal Gtl2-Rian-Mirg Locus by Preventing De Novo DNA Methylation in Mouse Embryonic Stem Cells.

Project description:Polycomb Repressive Complex 2 (PRC2) function and DNA methylation (DNAme) are typically correlated with gene repression. Here, we show that PRC2 is required to maintain expression of maternal microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) from the Gtl2-Rian-Mirg locus, which is essential for full pluripotency of iPSCs. In the absence of PRC2, the entire locus becomes transcriptionally repressed due to gain of DNAme at the intergenic differentially methylated regions (IG-DMRs). Furthermore, we demonstrate that the IG-DMR serves as an enhancer of the maternal Gtl2-Rian-Mirg locus. Further analysis reveals that PRC2 interacts physically with Dnmt3 methyltransferases and reduces recruitment to and subsequent DNAme at the IG-DMR, thereby allowing for proper expression of the maternal Gtl2-Rian-Mirg locus. Our observations are consistent with a mechanism through which PRC2 counteracts the action of Dnmt3 methyltransferases at an imprinted locus required for full pluripotency.

| S-EPMC5384103 | biostudies-literature

Polycomb PRC2 antagonizes de novo DNA methylation at the maternal Gtl2-Rian-Mirg locus

Project description:Polycomb PRC2 antagonizes de novo DNA methylation at the maternal Gtl2-Rian-Mirg locus

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Hypermethylation and reduced expression of Gtl2, Rian and Mirg at the Dlk1-Dio3 imprinted locus as a marker for poor developmental potential of mouse embryonic stem cells.

Project description:Mouse embryonic stem cells (ESCs) have played a crucial role in biomedical research where they can be used to elucidate gene function through the generation of genetically modified mice. A critical requirement for the success of this technology is the ability of ESCs to contribute to viable chimaeras with germ-line transmission of the genetically modified allele. We have identified several ESC clones that cause embryonic death of chimaeras at mid to late gestation stages. These clones had a normal karyotype, were pathogen free and their in vitro differentiation potential was not compromised. Chimaeric embryos developed normally up to E13.5 but showed a significant decrease in embryo survival by E17.5 with frequent haemorrhaging. We investigated the relationship between the ESCs transcriptional and epigenomic state and their ability to contribute to viable chimaeras. RNA sequencing identified four genes (Gtl2, Rian, Mirg and Rtl1as) located in the Dlk1-Dio3 imprinted locus that were expressed at lower levels in the compromised ESC clones and this was confirmed by qRT-PCR. Bisulphite sequencing analysis showed significant hypermethylation at the Dlk1-Dio3 imprinted locus with no consistent differences in methylation patterns at other imprinted loci. Treatment of the compromised ESCs with 5-azacytidine reactivated stable expression of Gtl2 and rescued the lethal phenotype but only gave low level chimaeras.

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Overexpression of microRNAs from the Gtl2-Rian locus contributes to postnatal death in mice.

Project description:The Dlk1-Dio3 imprinted domain functions in embryonic development but the roles of noncoding RNAs expressed from this domain remain unclear. We addressed this question by generating transgenic (TG) mice harbouring a BAC carrying IG-DMR (intergenic-differentially methylated region), Gtl2-DMR, Gtl2, Rtl1/Rtl1as, and part of Rian. High postnatal lethality (>85%) of the BAC-TG pups was observed in the maternally transmitted individuals (MAT-TG), but not following paternal transmission (PAT-TG). The DNA methylation status of IG-DMR and Gtl2-DMR in the BAC-allele was paternally imprinted similar to the genomic allele. The mRNA-Seq and miRNA-Seq analysis revealed marked expression changes in the MAT-TG, with 1,500 upregulated and 2,131 downregulated genes. The long noncoding RNAs and 12 miRNAs containing the BAC locus were markedly enhanced in the MAT-TG. We identified the 24 target genes of the overexpressed miRNAs and confirmed the downregulation in the MAT-TG. Notably, overexpression of mir770, mir493, and mir665 from Gtl2 in the MAT-TG embryos led to decreased expression of the 3 target genes, Col5a1, Pcgf2, and Clip2. Our results suggest that decreased expression of the 3 target genes concomitant with overexpression of the miRNAs within Gtl2 may be involved in the postnatal death in the MAT-TG. Because this imprinted domain is well conserved between mice and humans, the results of genetic and molecular analysis in mice hold important implications for related human disorders such as Temple syndrome.

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PRMT5-mediated histone arginine methylation antagonizes transcriptional repression by polycomb complex PRC2.

Project description:Protein arginine methyltransferase 5 (PRMT5) catalyzes the symmetric di-methylation of arginine residues in histones H3 and H4, marks that are generally associated with transcriptional repression. However, we found that PRMT5 inhibition or depletion led to more genes being downregulated than upregulated, indicating that PRMT5 can also act as a transcriptional activator. Indeed, the global level of histone H3K27me3 increases in PRMT5 deficient cells. Although PRMT5 does not directly affect PRC2 enzymatic activity, methylation of histone H3 by PRMT5 abrogates its subsequent methylation by PRC2. Treating AML cells with an EZH2 inhibitor partially restored the expression of approximately 50% of the genes that are initially downregulated by PRMT5 inhibition, suggesting that the increased H3K27me3 could directly or indirectly contribute to the transcription repression of these genes. Indeed, ChIP-sequencing analysis confirmed an increase in the H3K27me3 level at the promoter region of a quarter of these genes in PRMT5-inhibited cells. Interestingly, the anti-proliferative effect of PRMT5 inhibition was also partially rescued by treatment with an EZH2 inhibitor in several leukemia cell lines. Thus, PRMT5-mediated crosstalk between histone marks contributes to its functional effects.

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Hypermethylation and reduced expression of Gtl2, Rian and Mirg at the Dlk1-Dio3 imprinted locus as a marker for poor developmental potential of mouse embryonic stem cells

2020-05-01 | GSE149628 | GEO