Morphine leads to global genome changes of H3K27me3 levels in mESCs by a self-regulatory mechanism of Polycomb Repressive Complex 2 (PRC2)
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ABSTRACT:
PROVIDER: PRJNA635171 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11852061.fastq.gz | Fastqsanger.gz | |||
| SRR11852062.fastq.gz | Fastqsanger.gz | |||
| SRR11852063.fastq.gz | Fastqsanger.gz | |||
| SRR11852064.fastq.gz | Fastqsanger.gz | |||
| SRR11852065.fastq.gz | Fastqsanger.gz |
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Project description:Environmentally induced epigenetic changes can lead to health problems or disease, but the mechanisms involved remain unclear. Morphine can pass through the placental barrier leading to abnormal embryo development. However, the mechanism by which morphine causes these effects and how the sometimes persist into the adulthood is not well known. To unravel the morphine-induced chromatin alterations involved in aberrant embryo development, we explore the role of H3K27me3/PRC2 repressive complex in gene expression and its transmission across cellular generations in response to morphine. Using mouse embryonic stem cells as a model system, we find that chronic morphine treatment (24h) induces a global down-regulation of the histone modification H3K27me3. Conversely, ChIP-seq showed a remarkable increase in H3K27me3 levels at certain genomic sites, particularly promoters, disrupting selective target genes related to embryo development, cell cycle and metabolism. By a self-regulatory mechanism, transcription of components of the PRC2 complex responsible for H3K27me3 methylation, were consistently down-regulated by morphine, with high promoter levels of H3K27me3. Down-regulation of PRC2 components persisted for at least 48h (4 cell cycles) following morphine removal, though promoter H3K27me3 returned to control levels. Morphine induces targeting of PRC2 complex to selected promoters, including those of PRC2 components, leading to characteristic changes in gene expression and global reduction in H3K27me3. Following morphine removal, enhanced promoter H3K227me3 levels revert to normal sooner than global H3K27me3 or transcript levels of PRC2 components. We suggest that H3K27me3 is involved in initiating morphine induced changes in gene expression but not in their maintenance.
2020-11-16 | GSE151234 | GEO
Project description:BackgroundEnvironmentally induced epigenetic changes can lead to health problems or disease, but the mechanisms involved remain unclear. Morphine can pass through the placental barrier leading to abnormal embryo development. However, the mechanism by which morphine causes these effects and how they sometimes persist into adulthood is not well known. To unravel the morphine-induced chromatin alterations involved in aberrant embryo development, we explored the role of the H3K27me3/PRC2 repressive complex in gene expression and its transmission across cellular generations in response to morphine.ResultsUsing mouse embryonic stem cells as a model system, we found that chronic morphine treatment induces a global downregulation of the histone modification H3K27me3. Conversely, ChIP-Seq showed a remarkable increase in H3K27me3 levels at specific genomic sites, particularly promoters, disrupting selective target genes related to embryo development, cell cycle and metabolism. Through a self-regulatory mechanism, morphine downregulated the transcription of PRC2 components responsible for H3K27me3 by enriching high H3K27me3 levels at the promoter region. Downregulation of PRC2 components persisted for at least 48 h (4 cell cycles) following morphine removal, though promoter H3K27me3 levels returned to control levels.ConclusionsMorphine induces targeting of the PRC2 complex to selected promoters, including those of PRC2 components, leading to characteristic changes in gene expression and a global reduction in H3K27me3. Following morphine removal, enhanced promoter H3K27me3 levels revert to normal sooner than global H3K27me3 or PRC2 component transcript levels. We suggest that H3K27me3 is involved in initiating morphine-induced changes in gene expression, but not in their maintenance. Model of Polycomb repressive complex 2 (PRC2) and H3K27me3 alterations induced by chronic morphine exposure. Morphine induces H3K27me3 enrichment at promoters of genes encoding core members of the PRC2 complex and is associated with their transcriptional downregulation.
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Project description:Polycomb Repressive Complexes PRC1 and PRC2 play a crucial role in silencing lineage-specific genes during early embryogenesis. To provide new insights in polycomb biology, we profiled the proximal interactome (proxeome) of the catalytic subunits RNF2 (PRC1) and EZH2 (PRC2) in mouse embryonic stem cells (mESCs). This revealed >100 proteins proximal to PRC12 and PRC21, which mainly comprise transcription factors, transcriptional regulators and RNA binding proteins. To investigate the link between PRC2 and NuA4, and therefore the the link between H4ac an H3K27me3, we perturbed PRC2 both chemically and genetically.The effects on the histone PTMs were measured with LC-MS/MS.
2025-02-25 | PXD048246 | Pride
Project description:Polycomb Repressive Complexes PRC1 and PRC2 play a crucial role in silencing lineage-specific genes during early embryogenesis. To provide new insights in polycomb biology, we profiled the proximal interactome (proxeome) of the catalytic subunits RNF2 (PRC1) and EZH2 (PRC2) in mouse embryonic stem cells (mESCs). This revealed >100 proteins proximal to PRC2 and PRC1, which mainly comprise transcription factors, transcriptional regulators and RNA binding proteins. Interestingly, the EZH2 proxeome included both PRC complexes, while the RNF2 proxeome only identified PRC1 subunits. More than half of the PRC2 proximal proteins are shared with PRC1, revealing the molecular constitution of polycomb chromatin domains. We identified several pluripotency-associated transcription factors, including NANOG, for which we confirmed genomic co-localisation with PRC2. Upon PRC2 disruption, NANOG redistributes to specific sites containing its DNA binding motif. Finally, we compared PRC2 proximal interactomes between naïve mESCs, serum-cultured mESCs and embryoid bodies, altogether providing a comprehensive resource in different cellular contexts that may help to further decipher Polycomb biology.
2025-02-25 | PXD058327 | Pride
Project description:Polycomb Repressive Complexes PRC1 and PRC2 play a crucial role in silencing lineage-specific genes during early embryogenesis. To provide new insights in polycomb biology, we profiled the proximal interactome (proxeome) of the catalytic subunits RNF2 (PRC1) and EZH2 (PRC2) in mouse embryonic stem cells (mESCs). This revealed >100 proteins proximal to PRC2 and PRC1, which mainly comprise transcription factors, transcriptional regulators and RNA binding proteins. Interestingly, the EZH2 proxeome included both PRC complexes, while the RNF2 proxeome only identified PRC1 subunits. More than half of the PRC2 proximal proteins are shared with PRC1, revealing the molecular constitution of polycomb chromatin domains. We identified several pluripotency-associated transcription factors, including NANOG, for which we confirmed genomic co-localisation with PRC2. Upon PRC2 disruption, NANOG redistributes to specific sites containing its DNA binding motif. Finally, we compared PRC2 proximal interactomes between naïve mESCs, serum-cultured mESCs and embryoid bodies, altogether providing a comprehensive resource in different cellular contexts that may help to further decipher Polycomb biology.
2025-02-25 | PXD047569 | Pride
Project description:Polycomb proteins are epigenetic regulators that localize to developmental loci in the early embryo where they mediate lineage-specific gene repression. In Drosophila, these repressors are recruited to sequence elements by DNA binding proteins associated with Polycomb repressive complex 2 (PRC2). However, the sequences that recruit PRC2 in mammalian cells have remained obscure. To address this, we integrated a series of engineered bacterial artificial chromosomes into embryonic stem (ES) cells and examined their chromatin. We found that a 44 kb region corresponding to the Zfpm2 locus initiates de novo recruitment of PRC2. We then pinpointed a CpG island within this locus as both necessary and sufficient for PRC2 recruitment. Based on this causal demonstration and prior genomic analyses, we hypothesized that large GC-rich elements depleted of activating transcription factor motifs mediate PRC2 recruitment in mammals. We validated this model in two ways. First, we showed that a constitutively active CpG island is able to recruit PRC2 after excision of a cluster of activating motifs. Second, we showed that two 1 kb sequence intervals from the E. coli genome with GC-contents comparable to a mammalian CpG island are both capable of recruiting PRC2 when integrated into the ES cell genome. Our findings demonstrate a causal role for GC-rich sequences in PRC2 recruitment and implicate a specific subset of CpG islands depleted of activating motifs as instrumental for the initial localization of this key regulator in mammalian genomes. Analysis of YY1 binding in two cell types
2010-11-23 | E-GEOD-25197 | biostudies-arrayexpress
Project description:Polycomb group (PcG) proteins are required for normal differentiation and development, and their activity is found deregulated in cancer. PcG proteins are involved in gene silencing, however, whether they initiate or maintain transcriptional repression is a subject of debate. Here, we show that knockout of the Polycomb repressive complex 2 (PRC2) does not lead to significant gene expression changes in mouse embryonic stem cells (mESCs), and that it is dispensable for initiating silencing of target genes during differentiation. Transcriptional inhibition in mESCs is sufficient to induce genome-wide ectopic PRC2 recruitment to endogenous PcG target genes found in other tissues. PRC2 binding analysis shows that it is restricted to nucleosome-free CpG islands (CGIs) of un-transcribed genes. Our results show that it is the transcriptional state that governs PRC2 binding, and we propose that it binds by default to non-transcribed CGI genes to maintain their silenced state and to protect cell identity. Input from ChIP-seq experiment in Mus musculus wild-type E14 Embryonic Stem Cells.
2014-07-03 | E-GEOD-58022 | biostudies-arrayexpress
Project description:Polycomb group (PcG) proteins are required for normal differentiation and development, and their activity is found deregulated in cancer. PcG proteins are involved in gene silencing, however, whether they initiate or maintain transcriptional repression is a subject of debate. Here, we show that knockout of the Polycomb repressive complex 2 (PRC2) does not lead to significant gene expression changes in mouse embryonic stem cells (mESCs), and that it is dispensable for initiating silencing of target genes during differentiation. Transcriptional inhibition in mESCs is sufficient to induce genome-wide ectopic PRC2 recruitment to endogenous PcG target genes found in other tissues. PRC2 binding analysis shows that it is restricted to nucleosome-free CpG islands (CGIs) of un-transcribed genes. Our results show that it is the transcriptional state that governs PRC2 binding, and we propose that it binds by default to non-transcribed CGI genes to maintain their silenced state and to protect cell identity. Suz12, H3K27me3 and RNAPII ChIP-seq experiments before and after transcriptional inhibition with either DRB (0h, 6h and 12h) or Triptolide (0h, 3h and 9h) treatment of Mus musculus wild-type E14 Embryonic Stem Cells with up to two biological replicates per condition.
2014-07-03 | E-GEOD-58019 | biostudies-arrayexpress
Project description:Polycomb group (PcG) proteins are required for normal differentiation and development, and their activity is found deregulated in cancer. PcG proteins are involved in gene silencing, however, whether they initiate or maintain transcriptional repression is a subject of debate. Here, we show that knockout of the Polycomb repressive complex 2 (PRC2) does not lead to significant gene expression changes in mouse embryonic stem cells (mESCs), and that it is dispensable for initiating silencing of target genes during differentiation. Transcriptional inhibition in mESCs is sufficient to induce genome-wide ectopic PRC2 recruitment to endogenous PcG target genes found in other tissues. PRC2 binding analysis shows that it is restricted to nucleosome-free CpG islands (CGIs) of un-transcribed genes. Our results show that it is the transcriptional state that governs PRC2 binding, and we propose that it binds by default to non-transcribed CGI genes to maintain their silenced state and to protect cell identity. in vivo Trancription Capture-sequencing (iTC-seq) time-course experiments during transcriptional inhibition with either DRB (0h, 2h and 5h) or Triptolide (0h, 1h and 2h) treatment of Mus musculus wild-type E14 Embryonic Stem Cells with two biological replicates per condition.
2014-07-03 | E-GEOD-58018 | biostudies-arrayexpress
Project description:Polycomb group (PcG) proteins are required for normal differentiation and development, and their activity is found deregulated in cancer. PcG proteins are involved in gene silencing, however, whether they initiate or maintain transcriptional repression is a subject of debate. Here, we show that knockout of the Polycomb repressive complex 2 (PRC2) does not lead to significant gene expression changes in mouse embryonic stem cells (mESCs), and that it is dispensable for initiating silencing of target genes during differentiation. Transcriptional inhibition in mESCs is sufficient to induce genome-wide ectopic PRC2 recruitment to endogenous PcG target genes found in other tissues. PRC2 binding analysis shows that it is restricted to nucleosome-free CpG islands (CGIs) of un-transcribed genes. Our results show that it is the transcriptional state that governs PRC2 binding, and we propose that it binds by default to non-transcribed CGI genes to maintain their silenced state and to protect cell identity. RNA-seq time-course experiments during in vitro differentiation (0h, 24h, 48h and 72h) of Mus musculus wild-type E14 and Suz12 knock-out Embryonic Stem Cells with two biological replicates per condition.
2014-07-03 | E-GEOD-58017 | biostudies-arrayexpress