PRC2 controls adult neuron identity and protects neurons against neurodegeneration
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ABSTRACT:
PROVIDER: PRJNA328466 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-07-29 | E-GEOD-84245 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-07-29 | GSE84245 | GEO
Project description:Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD), leading to earlier age of clinical onset and exacerbating pathologies. There is a critical need to identify protective targets. Recently, a rare APOE variant, APOE3-R136S (Christchurch), was found to protect against early-onset AD in a PSEN1-E280A carrier. We sought to determine if the R136S mutation also protects against APOE4-driven effects in LOAD. We generated tauopathy mouse and human iPSC-derived neuron models carrying human APOE4 with the homozygous or heterozygous R136S mutation. We found that the homozygous R136S mutation rescued APOE4-driven Tau pathology, neurodegeneration, and neuroinflammation. The heterozygous R136S mutation partially protected against APOE4-driven neurodegeneration and neuroinflammation, but not Tau pathology. Single-nucleus RNA-sequencing revealed that the APOE4-R136S mutation increased disease-protective and diminished disease-associated cell populations in a gene dose-dependent manner. Thus, the APOE-R136S mutation protects against APOE4-driven AD pathologies, providing a target for therapeutic development against AD.
2023-09-21 | GSE217854 | 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 | 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 | GSE189328 | GEO
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.
2019-12-25 | GSE124580 | GEO
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.
2013-10-25 | E-GEOD-50951 | biostudies-arrayexpress
Project description:Dentatorubral-pallidoluysian Atrophy (DRPLA) is a human polyQ disease caused by the expansion of a CAG strech in the atrophin-1 (at-1) gene. In all vertebrates, a second atrophin gene (at-2) is present and it encodes a related protein void of polyQ tracks. In D.melanogaster there is one conserved Atrophin (Atro) gene, ubiquitously expressed, which contains all functional domains of vertebrate Atrophins, including two polyQ stretches. To understand to what extent transcriptional alterations cause neurodegeneration and are linked to the normal functions of Atrophin, we performed a genome wide transcriptional profiling in our Drosophila models, focusing on primary events that precede neurodegeneration. We have found that polyQ Atro downregulates fat, which protects from neurodegeneration and Atrophin toxicity trhough the Hippo kinase cascade. Neurodegeneration progression caused by poly glutamine expansions of the Atro gene is measured by mRNA expression profiles in 4 D.melanogaster genotypes: in wild-type animals (controls), animals constitutively expressing the wild-type Atro transgene, animals constitutively expressing the polyQ expanded Atro transgenes A66QC and A75QN. The expressions of the Atro genes are under a GMR-Gal4 driver repressed by a Gal80 universal repressor sensitive to temperature. When flies are raised at 18 C, the transgenes are not expressed, but their expression is switched on when they are shifted to the ageing protocol at 29 C at time point day 0. The neurodegeneration is assessed after 2 and 14 days post-high-temperature shift.
2011-03-01 | E-GEOD-26246 | biostudies-arrayexpress
Project description:The mammalian telencephalon contains a tremendous diversity of GABAergic projection neuron and interneuron types, that originate in a germinal zone of the embryonic basal ganglia. How genetic information in this transient structure is transformed into different cell types is not yet fully understood. Using a combination of in vivo lineage tracing, CRISPR perturbation and ChIP-seq in mice, we found that the transcription factor MEIS2 favors the development of projection neurons through genomic binding sites in regulatory enhancers of projection neuron specific genes. MEIS2 requires the presence of the homeodomain transcription factor DLX5 to direct its functional activity towards these sites. In interneurons, the activation of projection neuron specific enhancers by MEIS2 and DLX5 is repressed by the transcription factor LHX6. When MEIS2 carries a mutation associated with intellectual disability in humans, it is less effective at activating enhancers involved in projection neuron development. This suggests that GABAergic differentiation may be impaired in patients carrying this mutation. Our research has uncovered a mechanism by which the selective activation of enhancers plays a crucial role in the establishment of neuronal identity, as well as in potential pathological mechanisms
2024-02-19 | GSE231774 | GEO