Switching from Random to Imprinted X-inactivation by Maternal PRC2
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA507766 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8267530_1.fastq.gz | Fastqsanger.gz | |||
| SRR8267530_2.fastq.gz | Fastqsanger.gz | |||
| SRR8267540_1.fastq.gz | Fastqsanger.gz | |||
| SRR8267540_2.fastq.gz | Fastqsanger.gz | |||
| SRR8267531_1.fastq.gz | Fastqsanger.gz |
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Project description:Imprinted X-inactivation is a paradigm of transgenerational epigenetic inheritance in mammals and silences genes exclusively on the paternally-inherited X-chromosome. Here, we test the hypothesis that oocyte-derived maternal Polycomb repressive complex 2 (PRC2) protein EED orchestrates the selective inactivation of the paternal-X in mouse embryos. In maternal Eed null (Eedm-/-) but not zygotic Eed null female and male embryos, the maternal X-chromosome ectopically induced Xist lncRNA, which silences X-linked genes. Subsequently, Xist was silenced from one of the two X-chromosomes in females and from the sole maternal-X in males. As a result, later-stage female Eedm-/- embryos displayed random X-inactivation. The kinetics of Xist RNA induction in Eedm-/- embryos resemble that of early human embryos, which lack oocyte-derived PRC2 and only undergo random X-inactivation. Thus, expression of PRC2 genes in the oocyte and transmission of the gene products to the embryo may dictate the occurrence of imprinted X-inactivation in mammals.
2019-05-02 | GSE123173 | GEO
Project description:Imprinted X-inactivation silences genes exclusively on the paternally-inherited X-chromosome and is a paradigm of transgenerational epigenetic inheritance in mammals. Here, we test the role of maternal vs. zygotic Polycomb repressive complex 2 (PRC2) protein EED in orchestrating imprinted X-inactivation in mouse embryos. In maternal-null (Eedm-/-) but not zygotic-null (Eed-/-) early embryos, the maternal X-chromosome ectopically induced Xist and underwent inactivation. Eedm-/- females subsequently stochastically silenced Xist from one of the two X-chromosomes and displayed random X-inactivation. This effect was exacerbated in embryos lacking both maternal and zygotic EED (Eedmz-/-), suggesting that zygotic EED can also contribute to the onset of imprinted X-inactivation. Xist expression dynamics in Eedm-/- embryos resemble that of early human embryos, which lack oocyte-derived maternal PRC2 and only undergo random X-inactivation. Thus, expression of PRC2 in the oocyte and transmission of the gene products to the embryo may dictate the occurrence of imprinted X-inactivation in mammals.
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Project description:Genomic imprinting is essential for mammalian development. Recent studies have revealed that maternal histone H3 lysine 27 tri-methylation (H3K27me3) can mediate DNA methylation-independent genomic imprinting. However, the regulatory mechanisms and functions of this new imprinting mechanism are largely unknown. Here we demonstrate that maternal Eed, an essential component of the Polycomb group complex 2 (PRC2), is required for establishing H3K27me3 imprinting. We found that all H3K27me3 imprinted genes, including Xist, lose their imprinted expression in Eed maternal KO (matKO) embryos, resulting in male-biased lethality. Surprisingly, although maternal X chromosome inactivation (XmCI) occurs in Eed matKO embryos at preimplantation due to loss of Xist imprinting, it is resolved at peri-implantation. Ultimately, both X chromosomes are reactivated in the embryonic cell lineage prior to random XCI, and only a single X chromosome undergoes random XCI in the extra-embryonic cell lineage. Thus, our study not only demonstrates an essential role of Eed in H3K27me3 imprinting establishment but also reveals a unique XCI dynamics in the absence of Xist imprinting.
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Project description:In mice, imprinted X-chromosome inactivation (iXCI) of the paternal X in the pre-implantation embryo and extra-embryonic tissues is followed by X-reactivation in the epiblast precursors of the inner cell mass (ICM) of the blastocyst, to facilitate initiation of random XCI (rXCI) in all embryonic tissues. RNF12 is an E3 ubiquitin-ligase that plays a key role in XCI. RNF12 targets pluripotency protein REX1 for degradation to initiate rXCI in embryonic stem cells (ESCs) and loss of the maternal copy of Rnf12 leads to embryonic lethality due to iXCI failure. Here, we show that loss of Rex1 rescues the rXCI phenotype observed in Rnf12-/- ESCs, and that REX1 is the prime target of RNF12 in ESCs. Genetic ablation of Rex1 in Rnf12-/- mice rescues the Rnf12-/- iXCI phenotype, and results in viable and fertile Rnf12-/-:Rex1-/- female mice displaying normal iXCI and rXCI. Our results show that REX1 is the critical target of RNF12 in XCI.
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Project description:Maternal SMCHD1 controls both imprinted Xist expression and imprinted X chromosome inactivation
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Project description:Embryonic development is dependent on the maternal supply of proteins through the oocyte, including factors setting up the adequate epigenetic patterning of the zygotic genome. We previously reported that one such factor is the epigenetic repressor SMCHD1, whose maternal supply controls autosomal imprinted expression in mouse preimplantation embryos and mid-gestation placenta. In mouse preimplantation embryos, X chromosome inactivation is also an imprinted process. Combining genomics and imaging, we show that maternal SMCHD1 is required not only for the imprinted expression of Xist in preimplantation embryos, but also for the efficient silencing of the inactive X in both the preimplantation embryo and mid-gestation placenta. These results expand the role of SMCHD1 in enforcing the silencing of Polycomb targets. The inability of zygotic SMCHD1 to fully restore imprinted X inactivation further points to maternal SMCHD1's role in setting up the appropriate chromatin environment during preimplantation development, a critical window of epigenetic remodelling.
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Project description:Dynamic Erasure of Random X-Chromosome Inactivation during iPSC Reprogramming
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Project description:In Mammals, the difference in sex-chromosome constitution between males (XY) and females (XX) has led to the evolution of dosage compensation strategies, including silencing of an entire X chromosome in females. In mice, X chromosome inactivation (XCI) first occurs in the pre-implantation embryo. Here the non-coding Xist RNA is expressed only from the paternal allele and the paternal X (Xp) becomes inactivated. The Xp is reactivated in the inner cell mass and this is followed by random XCI in the embryo proper, while in extra-embryonic tissues the Xp remains inactive. Although random XCI initiation is thought to be fully Xist-dependent in the mouse, initiation of imprinted XCI was reported to be Xist-independent. Furthermore, the chromosome-wide dynamics of XCI in early embryos of reciprocal inter-specific crosses, which better reflect a natural situation, have never been investigated. Here we report that the expression dynamics of X-linked genes depends both on strain and parent of origin, as well as on X chromosome location, using single-cell RNA-sequencing (scRNAseq) of early mouse embryos. We also demonstrate that initiation of imprinted XCI absolutely requires Xist and that its absence leads to genome-wide transcriptional misregulation in the early blastocyst, with massive over-expression of specific genes such as Rhox5 and failure to activate the extra-embryonic pathway essential for early post-implantation development. This study provides important insights into the transcriptional and allelic dynamics of the X chromosome and the first evidence of dosage compensation failure as early as the blastocyst stage.
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Project description:Many host-adapted bacterial pathogens contain DNA methyltransferases (mod genes) that are subject to phase-variable expression (high-frequency reversible ON/OFF switching of gene expression). In Haemophilus influenzae, Neissera Meningtidis and Neisseria Gonorrhoeae, the random switching of the modA gene, associated with a phase variable type III restriction modification (R-M) system, controls expression of a phase-variable regulon of genes (a M-bM-^@M-^\phasevarionM-bM-^@M-^]), via differential methylation of the genome in the modA ON and OFF states. Phase variable type III R-M systems are also found in Helicobacter pylori, suggesting that phasevarions may also exist in this intriguing pathogen. Phylogenetic studies on the phase-variable type III modC gene revealed that there are 12 distinct alleles in H. pylori, which differ only in their DNA recognition domain, with the majority containing the C5 allele. Microarray analysis comparing the H. pylori wild-type P12modC5 ON strain to the P12(delta)modC5 mutant revealed that six genes were either up-regulated or down-regulated, some of which were virulence-associated. For example flaA, which encodes a flagella protein important in motility and hopG, which encodes an important outer membrane protein. This study, in conjunction with our previous work, indicates that phasevarions may be a common strategy used by host-adapted bacterial pathogens to randomly switch between M-bM-^@M-^\differentiatedM-bM-^@M-^] cell types. Direct comparison of biological triplicates of wild type and mutant strains
2012-01-16 | E-GEOD-26759 | biostudies-arrayexpress
Project description:Many host-adapted bacterial pathogens contain DNA methyltransferases (mod genes) that are subject to phase-variable expression (high-frequency reversible ON/OFF switching of gene expression). In Haemophilus influenzae, Neissera Meningtidis and Neisseria Gonorrhoeae, the random switching of the modA gene, associated with a phase variable type III restriction modification (R-M) system, controls expression of a phase-variable regulon of genes (a “phasevarion”), via differential methylation of the genome in the modA ON and OFF states. Phase variable type III R-M systems are also found in Helicobacter pylori, suggesting that phasevarions may also exist in this intriguing pathogen. Phylogenetic studies on the phase-variable type III modC gene revealed that there are 12 distinct alleles in H. pylori, which differ only in their DNA recognition domain, with the majority containing the C5 allele. Microarray analysis comparing the H. pylori wild-type P12modC5 ON strain to the P12(delta)modC5 mutant revealed that six genes were either up-regulated or down-regulated, some of which were virulence-associated. For example flaA, which encodes a flagella protein important in motility and hopG, which encodes an important outer membrane protein. This study, in conjunction with our previous work, indicates that phasevarions may be a common strategy used by host-adapted bacterial pathogens to randomly switch between “differentiated” cell types.
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