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Diverse epigenetic mechanisms maintain parental imprints within the embryonic and extraembryonic lineages

ABSTRACT: Genomic imprinting and X chromosome inactivation (XCI) require epigenetic mechanisms to direct allele-specific expression. Despite their critical roles in embryonic development, how universal epigenetic regulators coordinate these specific tasks at single loci or across chromosome scales remains understudied. Here, we systematically disrupted essential epigenetic pathways within polymorphic F1 embryos to examine canonical and non-canonical genomic imprinting as well as X chromosome inactivation. We find that DNA methylation and Polycomb group repressors are both indispensable for autosomal imprinting, albeit at distinct gene sets. Moreover, the extraembryonic ectoderm relies on a broader spectrum of imprinting mechanisms, including non-canonical targeting of maternal endogenous retrovirus (ERV) driven promoters by the H3K9 methyltransferase G9a. We further utilize our data to identify Polycomb dependent and independent gene clusters on the imprinted X chromosome, which appears to reflect distinct domains of Xist-mediated suppression. From our data, we assemble a comprehensive inventory of the epigenetic mechanisms utilized in eutherian mammals to maintain parent-specific imprinting, including an expanded view of the placental lineage that comprises multiple unique pathways.

ORGANISM(S): Mus musculus

PROVIDER: GSE171206 | GEO | 2021/11/12

REPOSITORIES: GEO

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Non-canonical imprinting ensures embryonic development and restrains placental overgrowth

Project description:Genomic imprinting regulates parental origin-dependent mono-allelic gene expression. It is mediated by either germline differential methylation of DNA (canonical imprinting) or oocyte-derived H3K27me3 (non-canonical imprinting) in mice. Depletion of Eed, an essential component of Polycomb repressive complex 2, results in genome-wide loss of H3K27me3 in oocytes, which causes loss of non-canonical imprinting (LOI) in embryos. Although Eed maternal KO (matKO) embryos show partial lethality after implantation, it is unknown whether LOI itself contributes to the developmental phenotypes of these embryos, which makes it unclear whether non-canonical imprinting is developmentally relevant. Here, by combinatorial matKO of Xist, a non-canonical imprinted gene whose LOI causes aberrant transient maternal X chromosome inactivation (XCI) at preimplantation, we show that prevention of the transient maternal XCI greatly restores the development of Eed matKO embryos. Moreover, we find that the placentae of Eed matKO embryos are remarkably enlarged in a manner independent of Xist LOI. Heterozygous deletion screening of individual autosomal non-canonical imprinted genes suggests that LOI of the Sfmbt2 miRNA cluster-chromosome 2 miRNA cluster (C2MC), solute carrier family 38 member 4 (Slc38a4), and Gm32885 contributes to the placental enlargement. Taken together, our study provides evidence that Xist imprinting sustains embryonic development and autosomal non-canonical imprinting restrains placental overgrowth.

2022-06-30 | GSE199115 | GEO

Maternal Eed knockout causes loss of H3K27me3 imprinting and random X-inactivation in the extra-embryonic cells

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.

2018-11-26 | GSE116713 | GEO

The role of Xist-mediated Polycomb recruitment in the initiation of X-chromosome inactivation

Project description:The role of Xist-mediated Polycomb recruitment in the initiation of X-chromosome inactivation

2019-08-29 | PXD014287 | Pride

Genome-wide Identification of Polycomb Target Genes Reveals a Functional Association of Pho with Scm in Bombyx mori

Project description:Polycomb group (PcG) proteins are involved in chromatin modifications for maintaining gene repression that play important roles in the regulation of gene expression, tumorigenesis, chromosome X-inactivation, and genomic imprinting in Drosophila melanogaster, mammals, and even plants. PcG proteins act together in three multimeric complexes, Polycomb repressive complex 1 (PRC1), Polycomb repressive complex 2 (PRC2), and Pleiohomeotic repressive complex (PhoRC), to repress transcription of the target genes. Here, we identified Polycomb target genes in Bombyx mori using genome-wide expression screening based on the knockdown of the BmSCE, BmESC, BmPHO, or BmSCM gene, which represent the distinct complexes. As a result, most genes were up-regulated after knocking down these four PcG genes, which indicated a potential epigenetic mechanism on the regulation of these genes expression by the PcG system. The further analysis of our data will provide some important information for the regulation mediated by PcG proteins in Bombyx mori. Transcription profiling experiments, knockdowns of four Polycomb genes (four samples) in silkworm BmN4-SID1 cells, were analyzed. Dual-channel experiments, with test samples labeled by Cy5 and common reference samples labeled by Cy3. The common reference sample, knockdown of the EGFP gene in BmN4-SID1 cells, was used for data normalization. One biological replicate. No dye-swaps.

2012-04-17 | E-GEOD-34246 | biostudies-arrayexpress

Polycomb-mediated repression of paternal chromosomes maintains haploid dosage in diploid embryos of Marchantia [RNA-seq]

Project description:Complex mechanisms regulate gene dosage throughout eukaryotic life cycles. Mechanisms controlling gene dosage have been extensively studied in animals, however it is unknown how generalizable these mechanisms are to diverse eukaryotes. Here, we use the haploid plant Marchantia polymorpha to assess gene dosage control in its short-lived diploid embryo. We show that throughout embryogenesis, paternal chromosomes are repressed resulting in functional haploidy. The paternal genome is targeted for genomic imprinting by the Polycomb mark H3K27me3 starting at fertilization, rendering the maternal genome in control of embryogenesis. Maintaining haploid gene dosage by this new form of imprinting is essential for embryonic development. Our findings illustrate how haploid-dominant species can regulate gene dosage through paternal chromosome inactivation and initiates the exploration of the link between life cycle history and gene dosage in a broader range of organisms.

2022-08-23 | GSE193306 | GEO

Polycomb-mediated repression of paternal chromosomes maintains haploid dosage in diploid embryos of Marchantia [CUT&RUN]

2022-08-23 | GSE193305 | GEO

Genome-wide Identification of Polycomb Target Genes Reveals a Functional Association of Pho with Scm in Bombyx mori

2012-04-18 | GSE34246 | GEO

A bipartite element with allele-specific functions safeguards DNA methylation imprints at the Dlk1-Dio3 locus [4C-seq]

Project description:Dysregulation of imprinted gene loci also referred to as loss of imprinting (LOI) can result in severe developmental defects and other diseases, but the molecular mechanisms that ensure imprint stability remain incompletely understood. Here, we dissect the functional components of the imprinting control region of the essential Dlk1-Dio3 locus (called IG-DMR) and the mechanism by which they ensure imprinting maintenance. Using pluripotent stem cells carrying an allele-specific reporter system, we demonstrate that the IG-DMR consists of two antagonistic regulatory elements: a paternally methylated CpG-island that prevents the activity of Tet dioxygenases and a maternally unmethylated regulatory element, which serves as a non-canonical enhancer and maintains expression of the maternal Gtl2 lncRNA by precluding de novo DNA methyltransferase function. Targeted genetic or epigenetic editing of these elements leads to LOI with either bi-paternal or bi-maternal expression patterns and respective allelic changes in DNA methylation and 3D chromatin topology of the entire Dlk1-Dio3 locus. Although the targeted repression of either IG-DMR or Gtl2 promoter is sufficient to cause LOI, the stability of LOI phenotype depends on the IG-DMR status, suggesting a functional hierarchy. These findings establish the IG-DMR as a novel type of bipartite control element and provide mechanistic insights into the control of Dlk1-Dio3 imprinting by allele-specific restriction of the active DNA (de)methylation machinery.

2021-09-14 | GSE148315 | GEO

Synergy between variant PRC1 complexes defines Polycomb-mediated gene repression (ChIP-Seq)

Project description:The Polycomb system modifies chromatin and plays an essential role in repressing gene expression to control normal mammalian development. However, the components and mechanisms that define how Polycomb protein complexes achieve this remain enigmatic. Here we use combinatorial genetic perturbation coupled with quantitative genomics to discover the central determinants of Polycomb-mediated gene repression in mouse embryonic stem cells. We demonstrate that canonical Polycomb repressive complex 1 (PRC1), which mediates higher order chromatin structures, contributes little to gene repression. Instead, we uncover an unexpectedly high degree of synergy between variant PRC1 complexes which is fundamental to gene repression. We further demonstrate that variant PRC1 complexes are responsible for distinct pools of H2A monoubiquitylation that are associated with repression of Polycomb target genes and silencing during X-chromosome inactivation. Together, these discoveries reveal a new variant PRC1-dependent logic for Polycomb-mediated gene repression.

2019-04-26 | GSE119618 | GEO

Profiling of differential allelic expression in horse, donkey, mule, and hinny placental tissues.

Project description:In eutherian mammals, dosage compensation of X-linked genes is achieved by X chromosome inactivation. X inactivation is random in embryonic and adult tissues, but imprinted X inactivation (paternal X silencing) has been identified in the extraembryonic membranes of the mouse, rat, and cow. Few other species have been studied for this trait, and the data from studies of the human placenta have been discordant or inconclusive. Here, we quantify X inactivation using RNA sequencing of placental tissue from reciprocal hybrids of horse and donkey (mule and hinny). In placental tissue from the equid hybrids and the horse parent the allelic expression pattern was consistent with random X inactivation, and imprinted X inactivation can clearly be excluded. We characterized horse and donkey XIST gene, and demonstrated that XIST allelic expression in female hybrid placental and fetal tissues is negatively correlated with the other X-linked genes chromosome-wide, which is consistent with the XIST-mediated mechanism of X inactivation discovered previously in mice. As the most structurally and morphologically diverse organ in mammals, the placenta also appears to show diverse mechanisms for dosage compensation that may result in differences in conceptus development across species. Examine allelic expression from individual samples of invasive trophoblast tissue of the chorionic girdle from gestation day 33-34 conceptuses of 5 horses, 3 donkeys, 6 mules, and 1 hinny.

2012-05-29 | E-GEOD-36352 | biostudies-arrayexpress

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