PRC2 controls adult neuron identity and protects neurons against neurodegeneration
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA328466 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3825151.fastq.gz | Fastqsanger.gz | |||
| SRR3825152.fastq.gz | Fastqsanger.gz | |||
| SRR3825153.fastq.gz | Fastqsanger.gz | |||
| SRR3825154.fastq.gz | Fastqsanger.gz | |||
| SRR3825155.fastq.gz | Fastqsanger.gz |
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2016-07-29 | E-GEOD-84245 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
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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.
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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.
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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.
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Project description:Here we have RNA binding protein DDX18 connecting rRNA transcription to early embryo development and embryonic stem cell (ESC) identity maintenance. DDX18 mutant embryos suffer lethality during preimplantation development. DDX18 depletion impairs ESC self-renewal and pluripotency, which phenotype-copies RNA polymerase I (RNAPI) inhibition. Mechanistically, DDX18 is recruited to rDNA by RNAPI transcription machinery and senses rRNA transcription by binding to pre-rRNA. In nucleolus, DDX18 surrounds DFC ring and interacts with PRC2. In the presence of transcribed pre-rRNA, DDX18 interaction with PRC2 makes EZH2 unstably binding to the other components of PRC2, thereby preventing PRC2 engagement and counteracting H3K27me3 mediated silencing at rDNA chromatin. Together, our study shows that DDX18 plays important roles in safeguarding ESCs identity through regulating epigenetic states of rDNA locus and maintaining euchromatin structure in nucleolus.
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Project description:The symptoms of ataxia-telangiectasia (A-T) include a progressive neurodegeneration caused by ATM protein deficiency. We previously found that nuclear accumulation of histone deacetylase-4, HDAC4, contributes to this degeneration; we now report that increased histone H3K27 trimethylation (H3K27me3) mediated by polycomb repressive complex 2 (PRC2) also plays an important role in the A-T phenotype. Enhancer of zeste homolog 2 (EZH2), a core catalytic component of PRC2, is identified as a new ATM kinase target, and its S734 phosphorylation reduces protein stability. Thus, PRC2 formation is elevated along with H3K27me3in ATM deficiency. ChIP-sequencing shows a significant increase in H3K27me3 ‘marks’ and a dramatic shift in their location. The change of H3K27me3 chromatin-binding pattern is directly related to cell cycle re-entry and cell death of ATM-deficient neurons. Lentiviral knockdown of EZH2 rescues Purkinje cell degeneration and behavioral abnormalities in Atm / mice, demonstrating that EZH2-mediated H3K27me3 is another key factor in A-T neurodegeneration. Two samples each were run of brain total RNA from Atm+/+ and Atm-/- mice.
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