EED-mediated histone methylation is critical for CNS myelination and remyelination by inhibiting WNT, BMP and senescence pathways
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE135880 | GEO | 2020/08/17
REPOSITORIES: GEO
Similar Datasets
Project description:Polycomb Repressive Complexes 1 and 2 (PRC1 and 2) play a critical role in the epigenetic regulation of transcription during cellular differentiation, stem cell pluripotency, and neoplastic progression1-3. Here we show that the Polycomb group protein EED, a core component of PRC2, physically interacts with and functions as part of the PRC1 complex. Components of PRC1 and PRC2 compete for EED binding. EED functions to recruit PRC1 to H3K27me3 loci and enhances PRC1 mediated H2A ubiquitin E3 ligase activity. Taken together, we uncover the integral role of EED as an epigenetic exchange factor coordinating the activities of PRC1 and 2. EED, uH2A, RING1A, RING1B, BMI1 and H3K27Me3 ChIP-seq in EED stable knockdown and control Scramble DU145 prostate cancer cell line
2014-01-23 | E-GEOD-42566 | biostudies-arrayexpress
Project description:In proliferating cells, where most Polycomb repressive complex 2 (PRC2) studies have been performed, gene repression is associated with PRC2 trimethylation of H3K27 (H3K27me3). However, it is uncertain whether PCR2 writing of H3K27me3 is mechanistically required for gene silencing. Here we studied PRC2 function in postnatal mouse cardiomyocytes, where the paucity of cell division obviates bulk H3K27me3 rewriting after each cell cycle. EED (Embryonic Ectoderm Development) inactivation in the postnatal heart (Eed CKO ) caused lethal dilated cardiomyopathy. Surprisingly, gene upregulation in Eed CKO was not coupled with loss of H3K27me3. Rather, the activating histone mark H3K27ac increased. EED interacted with histone deacetylases (HDACs) and enhanced their catalytic activity. HDAC overexpression normalized Eed CKO heart function and expression of derepressed genes. Our results uncovered a non-canonical, H3K27me3-independent EED repressive mechanism that is essential for normal heart function. Our results further illustrate that organ dysfunction due to epigenetic dysregulation can be corrected by epigenetic rewiring.
2017-04-14 | GSE73771 | GEO
Project description:Eed (embryonic ectoderm development) is a core component of the Polycomb Repressive Complex 2 (PRC2) which catalyzes the methylation of histone H3 lysine 27 (H3K27). Trimethylated H3K27 (H3K27me3) can act as a signal for PRC1 recruitment in the process of gene silencing and chromatin condensation. Previous studies with Eed KO ESCs revealed a failure to down-regulate a limited list of pluripotency factors in differentiating ESCs. Our aim was to analyze the consequences of Eed KO for ESC differentiation. To this end we first analyzed ESC differentiation in the absence of Eed and employed in silico data to assess pluripotency gene expression and H3K27me3 patterns. We linked these data to expression analyses of wildtype and Eed KO ESCs. We observed that in wildtype ESCs a subset of pluripotency genes including Oct4, Nanog, Sox2 and Oct4 target genes progressively gain H3K27me3 during differentiation. These genes remain expressed in differentiating Eed KO ESCs. This suggests that the deregulation of a limited set of pluripotency factors impedes ESC differentiation. Global analyses of H3K27me3 and Oct4 ChIP-seq data indicate that in ESCs the binding of Oct4 to promoter regions is not a general predictor for PRC2-mediated silencing during differentiation. However, motif analyses suggest a binding of Oct4 together with Sox2 and Nanog at promoters of genes that are PRC2-dependently silenced during differentiation. In summary, our data further characterize Eed function in ESCs by showing that Eed/PRC2 is essential for the onset of ESC differentiation. RNAs obtained from undifferentiated (d0) wild type and Eed KO ESCs and from day 3 (d3) and day 7 (d7) respective Ebs were subjected to Affymetrix Mouse Gene 1.0 ST Array. 24 samples in total.
2014-08-28 | E-GEOD-49305 | biostudies-arrayexpress
Project description:Eed (embryonic ectoderm development) is a core component of the Polycomb Repressive Complex 2 (PRC2) which catalyzes the methylation of histone H3 lysine 27 (H3K27). Trimethylated H3K27 (H3K27me3) can act as a signal for PRC1 recruitment in the process of gene silencing and chromatin condensation. Previous studies with Eed KO ESCs revealed a failure to down-regulate a limited list of pluripotency factors in differentiating ESCs. Our aim was to analyze the consequences of Eed KO for ESC differentiation. To this end we first analyzed ESC differentiation in the absence of Eed and employed in silico data to assess pluripotency gene expression and H3K27me3 patterns. We linked these data to expression analyses of wildtype and Eed KO ESCs. We observed that in wildtype ESCs a subset of pluripotency genes including Oct4, Nanog, Sox2 and Oct4 target genes progressively gain H3K27me3 during differentiation. These genes remain expressed in differentiating Eed KO ESCs. This suggests that the deregulation of a limited set of pluripotency factors impedes ESC differentiation. Global analyses of H3K27me3 and Oct4 ChIP-seq data indicate that in ESCs the binding of Oct4 to promoter regions is not a general predictor for PRC2-mediated silencing during differentiation. However, motif analyses suggest a binding of Oct4 together with Sox2 and Nanog at promoters of genes that are PRC2-dependently silenced during differentiation. In summary, our data further characterize Eed function in ESCs by showing that Eed/PRC2 is essential for the onset of ESC differentiation.
2014-08-28 | GSE49305 | GEO
Project description:To avoid exaggerated inflammation and injury, host cells adapt to become hypo-responsive or “tolerance” in response to successive exposure to stimuli. Such tolerized response is a part of innate immune memory which is mainly regulated via epigenetics changes and metabolic reprograming. Polycomb repressive complex 2 (PRC2) mediates the transcriptional repression by catalyzing histone H3 lysine 27 trimethylation (H3K27me3) but little is known about the roles of PRC2 in tolerant macrophages. We examined the impact of PRC2 components, EED and Ezh2, on lipopolysaccharide (LPS)-induced tolerant macrophages. In Eed KO macrophages, not only the significant reduction in H3K27me3, but also the augmentation of an active histone mark, H3K27Ac. Upon EED deletion but not Ezh2, macrophages exhibited attenuated pro-inflammatory cytokines productions (TNF-α and IL-6) in LPS-tolerant cells. In addition, LPS tolerant Eed KO macrophages exhibited low glycolytic activity rather than its littermate wild-type control. RNA-Seq analyses revealed that most of differentially expressed genes are involved in oxidative phosphorylation and TGF-β signaling. Alteration of H3K27me3 and H3K27ac in the regulatory regions of some of these genes were validated. These results indicated that PRC2 via EED epigenetically suppresses these genes in response to LPS re-exposure and lacking PRC2 activity results in hypo-responsive to LPS re-stimulation. Therefore, we provide strong evidences that PRC2 via EED mediates LPS tolerance in macrophages by epigenetically suppressing proinflammatory responses with the link to dysregulated metabolic pathway.
2023-06-20 | GSE234655 | GEO
Project description:Mutations in the polycomb repressive complex 2 (PRC2) can cause Weaver-like syndrome, wherein a patient cohort exhibits abnormal white matter; however, PRC2 functions in CNS myelination and regeneration remain elusive. We show here that H3K27me3, the PRC2 catalytic product, increases during oligodendrocyte maturation. Depletion of embryonic ectoderm development (EED), a core PRC2 subunit, reduces differentiation of oligodendrocyte progenitors (OPCs), and causes an OPC-to-astrocyte fate switch in a region-specific manner. Although dispensable for myelin maintenance, EED is critical for oligodendrocyte remyelination. Genomic occupancy and transcriptomic analyses indicate that EED establishes a chromatin landscape that selectively represses inhibitory WNT and bone morphogenetic protein (BMP) signaling, and senescence-associated programs. Blocking WNT or BMP pathways partially restores differentiation defects in EED-deficient OPCs. Thus, our findings reveal that EED/PRC2 is a crucial epigenetic programmer of CNS myelination and repair, while demonstrating a spatiotemporal-specific role of PRC2-mediated chromatin silencing in shaping oligodendrocyte identity and lineage plasticity.
| S-EPMC7423366 | biostudies-literature
Project description:EED-mediated histone methylation is critical for CNS myelination and remyelination by inhibiting WNT, BMP and senescence pathways
| PRJNA560396 | ENA
Project description:Through H3K27me3 and H3K27ac ChIP-seq and RNA-seq data in wile-tpye (WT) and EED-knockout (CKO) mouse cardiomyocytes, we unexpectedly uncovered a novel mechanism of PRC2-mediated gene repression. EED inactivation in the postnatal heart (EEDCKO) caused progressive, lethal dilated cardiomyopathy, with upregulation of components of the slow-twitch muscle gene program. Surprisingly, upregulation of these genes was not associated with their loss of H3K27me3, but rather with their gain of H3K27 acetylation (H3K27ac), an activating histone mark. Moreover, re-expression of EED in juvenile hearts rescued heart function and normalized H3K27ac, but not H3K27me3.
2017-04-14 | GSE89585 | GEO
Project description:Polycomb Repressive Complexes 1 and 2 (PRC1 and 2) play a critical role in the epigenetic regulation of transcription during cellular differentiation, stem cell pluripotency, and neoplastic progression1-3. Here we show that the Polycomb group protein EED, a core component of PRC2, physically interacts with and functions as part of the PRC1 complex. Components of PRC1 and PRC2 compete for EED binding. EED functions to recruit PRC1 to H3K27me3 loci and enhances PRC1 mediated H2A ubiquitin E3 ligase activity. Taken together, we uncover the integral role of EED as an epigenetic exchange factor coordinating the activities of PRC1 and 2.
2014-01-23 | GSE42566 | GEO
Project description:Extrinsic inhibitors at sites of blood-brain barrier (BBB) disruption and neurovascular damage contribute to remyelination failure in neurological diseases. However, therapies to overcome extrinsic inhibition of remyelination are not widely available and the dynamics of glial progenitor niche remodeling at site of neurovascular dysfunction are largely unknown. By integrating in vivo two-photon (2P) imaging co-registered with electron microscopy and transcriptomics in chronic neuroinflammatory lesions, we found repressed anticoagulation pathways in oligodendrocyte precursor cells (OPCs) that clustered perivascularly at sites of limited remyelination with deposition of fibrinogen, a blood coagulation factor abundantly deposited in multiple sclerosis lesions. By developing the OPC-X-screen to identify compounds that promote remyelination in the presence of extrinsic inhibitors, we showed that known promyelinating drugs did not rescue extrinsic inhibition of remyelination by fibrinogen. In contrast, bone morphogenetic protein (BMP) receptor blockade rescued the inhibitory fibrinogen effects and restored a promyelinating progenitor niche by promoting myelinating oligodendrocytes, while suppressing astrocyte cell fate with potent therapeutic effects in chronic models of multiple sclerosis. Thus, abortive OPC differentiation by fibrinogen is refractory to known promyelinating compounds, suggesting that blockade of the BMP signaling pathway may enhance remyelinating efficacy by overcoming extrinsic inhibition in neuroinflammatory lesions with vascular damage.
2021-08-24 | GSE166675 | GEO