H3K27me3 is dispensable for early differentiation but required to maintain differentiated cell identity
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ABSTRACT:
PROVIDER: PRJNA635937 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11879114.fastq.gz | Fastqsanger.gz | |||
| SRR11879115.fastq.gz | Fastqsanger.gz | |||
| SRR11879116.fastq.gz | Fastqsanger.gz | |||
| SRR11879117.fastq.gz | Fastqsanger.gz | |||
| SRR11879118.fastq.gz | Fastqsanger.gz |
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Project description:Polycomb repressive complex 2 (PRC2) catalyzes trimethylation of histone H3 on lysine 27 and is required for normal development of complex eukaryotes. The requirement for H3K27me3 in various aspects of mammalian differentiation is not clear. Though associated with repressed genes, the modification is not sufficient to induce gene repression, and in some instances is not required. To examine the role of the modification in mammalian differentiation, we blocked trimethylation of H3K27 with both a small molecule inhibitor, GSK343, and by introducing a point mutation into EZH2, the catalytic subunit of PRC2. We found that cells with substantively decreased H3K27 tri-methylation were able to differentiate, which contrasts with EZH2 null cells. Different PRC2 targets had varied requirements for K27me3 in repressive regulation with a subset that maintained normal levels of repression in the absence of methylation. The primary cellular phenotype where H3K27 tri-methylation was blocked was the inability of the altered cells to maintain a differentiated state when challenged. This phenotype depended upon H3K27me3 deposition both in embryonic stem cells and in the first four days of differentiation. H3K27 tri-methylation therefore was not necessary for formation of differentiated cell states but was required to maintain a stable differentiated state.
2021-03-26 | GSE151486 | GEO
Project description:Neurons of the CNS must maintain their distinct identity over an entire lifespan. Apart from instructive information provided by transcription factors driving neuron specific genes, other gene programs need to be permanently silenced. The mechanisms governing enduring gene-silencing in neurons are largely unknown, as are the consequences if they fail. Here we show that loss of the Polycomb repressive complex 2 (PRC2) obligate unit Eed in differentiated murine midbrain dopamine (mDA) neurons resulted in progressive loss of the H3K27me3 histone modification followed by upregulation of PRC2 targets, also highly enriched for the constitutive heterochromatin H3K9me3 modification. This was followed by reduced expression of mDA neuron-identity genes, particularly evident in the Substantia nigra pars compacta. Consequently, mDA-neuronal function was severely disrupted, causing parkinsonian-like motor skill deficits. Deletion of Eed in differentiated serotonergic (5HT) neurons resulted in a similar upregulation of PRC2-targets and reduced expression of genes defining 5HT neurons, which promoted loss of serotonergic identity followed by loss of function and altered behaviour. Overall, our results reveal that PRC2 inactivation leads to a selective and progressive loss of mDA or 5HT neuronal identity and function, but not to any loss of cells. Thus, our study shows that PRC2-dependent maintenance of neuronal identity is essential and safeguards against expression of other non-relevant gene programs and loss of neuronal function.
2022-07-11 | GSE189329 | GEO
Project description:Neurons of the CNS must maintain their distinct identity over an entire lifespan. Apart from instructive information provided by transcription factors driving neuron specific genes, other gene programs need to be permanently silenced. The mechanisms governing enduring gene-silencing in neurons are largely unknown, as are the consequences if they fail. Here we show that loss of the Polycomb repressive complex 2 (PRC2) obligate unit Eed in differentiated murine midbrain dopamine (mDA) neurons resulted in progressive loss of the H3K27me3 histone modification followed by upregulation of PRC2 targets, also highly enriched for the constitutive heterochromatin H3K9me3 modification. This was followed by reduced expression of mDA neuron-identity genes, particularly evident in the Substantia nigra pars compacta. Consequently, mDA-neuronal function was severely disrupted, causing parkinsonian-like motor skill deficits. Deletion of Eed in differentiated serotonergic (5HT) neurons resulted in a similar upregulation of PRC2-targets and reduced expression of genes defining 5HT neurons, which promoted loss of serotonergic identity followed by loss of function and altered behaviour. Overall, our results reveal that PRC2 inactivation leads to a selective and progressive loss of mDA or 5HT neuronal identity and function, but not to any loss of cells. Thus, our study shows that PRC2-dependent maintenance of neuronal identity is essential and safeguards against expression of other non-relevant gene programs and loss of neuronal function.
2022-07-11 | GSE189017 | GEO
Project description:Neurons of the CNS must maintain their distinct identity over an entire lifespan. Apart from instructive information provided by transcription factors driving neuron specific genes, other gene programs need to be permanently silenced. The mechanisms governing enduring gene-silencing in neurons are largely unknown, as are the consequences if they fail. Here we show that loss of the Polycomb repressive complex 2 (PRC2) obligate unit Eed in differentiated murine midbrain dopamine (mDA) neurons resulted in progressive loss of the H3K27me3 histone modification followed by upregulation of PRC2 targets, also highly enriched for the constitutive heterochromatin H3K9me3 modification. This was followed by reduced expression of mDA neuron-identity genes, particularly evident in the Substantia nigra pars compacta. Consequently, mDA-neuronal function was severely disrupted, causing parkinsonian-like motor skill deficits. Deletion of Eed in differentiated serotonergic (5HT) neurons resulted in a similar upregulation of PRC2-targets and reduced expression of genes defining 5HT neurons, which promoted loss of serotonergic identity followed by loss of function and altered behaviour. Overall, our results reveal that PRC2 inactivation leads to a selective and progressive loss of mDA or 5HT neuronal identity and function, but not to any loss of cells. Thus, our study shows that PRC2-dependent maintenance of neuronal identity is essential and safeguards against expression of other non-relevant gene programs and loss of neuronal function.
2022-07-11 | GSE189328 | GEO
Project description:Two distinct Polycomb complexes, PRC1 and PRC2, collaborate to maintain epigenetic repression of key developmental loci in embryonic stem cells (ESCs). PRC1 and PRC2 have histone modifying activities, catalyzing mono-ubiquitination of histone H2A (H2AK119u1) and trimethylation of H3 lysine 27 (H3K27me3) respectively. Compared to H3K27me3, localization and role of H2AK119ub1 is not fully understood in ESCs. Here we present genome-wide H2AK119u1 maps in ESCs and identify a group of genes at which H2AK119u1 is deposited in a Ring1-dependent manner. These genes are a distinctive subset of genes with H3K27me3 enrichment and are the central targets of Polycomb silencing that are required to maintain ESC identity. We further show that the H2A ubiquitination activity of PRC1 is dispensable for its target binding and its activity to compact chromatin at Hox loci, but is indispensable for efficient repression of target genes and thereby ESC maintenance. These data demonstrate that multiple effector mechanisms including H2A ubiquitination and chromatin compaction combine to mediate PRC1-dependent repression of genes that are crucial for the maintenance of ESC identity. Utilization of these diverse effector mechanisms might provide a means to maintain a repressive state that is robust yet highly responsive to developmental cues during ES cell self-renewal and differentiation. This SuperSeries is composed of the following subset Series: GSE38224: Expression data from Ring1A(-/-);Ring1B(fl/fl);R26::CreERT2 ES cells expressing either of mock, WT or mutant Ring1B construct before or after OHT treatment GSE38504: ChIP-on-chip analysis of Ring1B, Ring1A, H2AK119u1 and H3K27me3 in mouse ES cells Total RNAs were extracted from the respective ES cells, and were subjected to microarray analysis using Affymetrix GeneChip Mouse Genome 430A 2.0 arrays. ChIP on chip analysis was carried out using the Mouse Promoter ChIP-on-chip Microarray Set (G4490A, Agilent, Palo Alto, Calif., USA). MEFs were subjected to ChIP assay using various antibodies. Purified immunoprecipitated and input DNA was subjected to T7 RNA polymerase-based amplification. Labeling, hybridization and washing were carried out according to the Agilent mammalian ChIP-on-chip protocol (ver.9.0). Scanned images were quantified with Agilent Feature Extraction software under standard conditions.
2012-06-11 | E-GEOD-38650 | biostudies-arrayexpress
Project description:Two distinct Polycomb complexes, PRC1 and PRC2, collaborate to maintain epigenetic repression of key developmental loci in embryonic stem cells (ESCs). PRC1 and PRC2 have histone modifying activities, catalyzing mono-ubiquitination of histone H2A (H2AK119u1) and trimethylation of H3 lysine 27 (H3K27me3) respectively. Compared to H3K27me3, localization and role of H2AK119ub1 is not fully understood in ESCs. Here we present genome-wide H2AK119u1 maps in ESCs and identify a group of genes at which H2AK119u1 is deposited in a Ring1-dependent manner. These genes are a distinctive subset of genes with H3K27me3 enrichment and are the central targets of Polycomb silencing that are required to maintain ESC identity. We further show that the H2A ubiquitination activity of PRC1 is dispensable for its target binding and its activity to compact chromatin at Hox loci, but is indispensable for efficient repression of target genes and thereby ESC maintenance. These data demonstrate that multiple effector mechanisms including H2A ubiquitination and chromatin compaction combine to mediate PRC1-dependent repression of genes that are crucial for the maintenance of ESC identity. Utilization of these diverse effector mechanisms might provide a means to maintain a repressive state that is robust yet highly responsive to developmental cues during ES cell self-renewal and differentiation. This SuperSeries is composed of the SubSeries listed below.
2012-06-12 | GSE38650 | GEO
Project description:PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons
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Project description:PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons [ChIP-Seq]
| PRJNA781201 | ENA
Project description:PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons [snRNA-Seq]
| PRJNA782566 | ENA
Project description:We explored H3K27me3 binding sites in the genome of differentiated, conditionally immortalized mouse podocytes. Cells were allowed to differentiate for 14 days, following thermoshifting, before treatment with either vehicle (DMSO) or the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep, 5µM for 48 hours) which degrades the histone methyltransferase, EZH2 ordinarily responsible for H3K27 trimethylation (H3K27me3). DNA was immunopreciptated with an H3K27me3-specific antibody. Studying H3K27me3 modification in Mouse Podocyte
2015-12-09 | E-GEOD-69610 | biostudies-arrayexpress