ApoE maintains neuronal integrity via miRNA and H3K27me3-mediated repression [RNA-seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE198228 | GEO | 2024/01/29
REPOSITORIES: GEO
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Project description:To better understand the regulatory roles of ApoE in neurogenesis, we differentiated isogenic control and ApoE-/- human neural stem cells (NSC) into mature cortical neurons and cultured them for additional three weeks. In this study, we found that ApoE is only expressed in control NSC and neural progenitor cell (NPC) stages, but not in mature neurons, suggesting that ApoE may epigenetically regulate the integrity and maintenance of the mature neurons. Mechanistic studies revealed that absence of ApoE in NSC led to upregulation of certain microRNAs, including miR-199a-5p. These microRNAs targeted EZH1 to reduce its protein expression, resulting in the lower level of repressive H3K27me3 marks in ApoE-/- NPC and mature neurons. Chromatin immunoprecipitation experiments suggests that the lower level of H3K27me3 at various extracellular matrix organization and angiogenesis genes is responsible for their higher expression and aberrant phenotypes observed in ApoE-/- neurons. Taken together, our results indicate that ApoE maintains pure population of mature neurons via H3K27me3-mediated repression of genes that drive non-neuronal cell proliferation in NPC stage.
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2014-01-01 | E-GEOD-44532 | biostudies-arrayexpress
Project description:Adult neural progenitor cells (aNPCs) are a potential autologous cell source for cell replacement in neurologic diseases such as Parkinsonâs disease or stroke or for cell-based gene therapy for neurometabolic diseases. Easy accessibility, long-term expandability and detailed characterization of NPC properties are important requisites for their future translational/clinical applications. aNPC can be isolated from different regions of the adult human brain including the accessible subcortical white matter (aNPCWM), but systematic studies comparing long-term expanded aNPCWM with aNPC from neurogenic brain regions to check for their NPC characteristics and performance are not available. Freshly isolated cells from subcortical white matter and hippocampus (aNPCHIP) expressed oligodendrocyte progenitor cell (OPC) markers such as A2B5, NG2 and OLIG2 in ~20% of cells but no neural stem cell (NSC) markers such CD133 (Prominin1), NESTIN, SOX2 or PAX6. The EGF receptor (EGFR) protein was expressed in 18% of aNPCWM and 7% of aNPCHIP, but only a small fraction of 1 cell out 694 cells from white matter and only 1 out of 1,331 hippocampal cells were able to generate neurospheres. Studies comparing subcortical aNPCWM with their hippocampal counterparts showed that both NPC types expressed mainly markers of glial origin such as NG2, A2B5 and OLIG2, and the NSC/NPC marker Nestin, but no pericyte markers. Both NPC types were able to produce fully mature neurons, astrocytes and oligodendrocytes in comparable amounts to fetal NSC. Whole transcriptome analyses finally confirmed the strong similarity of aNPCWM with aNPCHIP. Our data show that aNPCWM are multipotent NPC with long-term expandability capacity similar to NPC from hippocampus making them an easily accessible source for possible autologous NPC-based treatment strategies. Isolation and propagation of multipotent NPCs. Adult human hippocampal (hip) and subcortical white matter (wm) tissue was obtained from routine epilepsy surgery procedures following informed consent of the subjects. All procedures were in accordance with the Helsinki convention and approved by the Ethical Committee of the University of Dresden (No. 47032006). All subjects underwent high-resolution magnetic resonance imaging excluding tumors and were screened for the presence of infectious disease. In all cases the neuropathological examinations did not reveal evidences for tumor formation. Gene expression Single-channel oligonucleotide microarray analysis. For the gene expression microarray analysis we used the Affimetrix U133A chips containing 22.215 probe sets representing at least 12.905 individual genes. The whole procedure was performed following the manufacturerâs standard protocol (Affimetrix, Santa Clara, CA). For the data processing, normalization was calculated with the GCRMA (GC content corrected Robust Multi-array Analysis) algorithm. fNSC: Human fetal neural stem cells, 2 biological rep aNPChip: Human adult neural progenitor cells isolated from hippocampus, 3 biological rep aNPCwm: Human adult neural progenitor cells isolated from white matter, 2 biological rep
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Project description:The generation of neocortical neurons from neural progenitor cells (NPCs) is primarily controlled by transcription factors binding to DNA in the context of chromatin. To understand the complex layer of regulation that orchestrates different NPC types from the same DNA sequence, epigenome maps with cell type resolution are required. Here we present genome-wide histone methylation maps for distinct neural cell populations in the developing mouse neocortex. Using different chromatin features, we identify potential novel regulators of cortical NPCs available for future exploration. Moreover, we identify extensive H3K27me3 changes between NPC subtypes coinciding with major developmental and cell biological transitions. Interestingly, we detect dynamic H3K27me3 changes on promoters of several crucial transcription factors, including the basal progenitor regulator Eomes. We used catalytically inactive Cas9 fused with the histone methyltransferase Ezh2 to edit H3K27me3 at the Eomes locus in vivo, which results in reduced Tbr2 expression and lower basal progenitor abundance, underscoring the relevance of dynamic H3K27me3 changes during neocortex development. Taken together, we provide a rich resource of neocortical histone methylation and outline an approach to investigate its contribution to the regulation of selected genes during neocortical development.
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Project description:H3K36me3 (ChIp-ChIp), H3K4me3 (ChIp-ChIp), H3K27me3 (ChIp-ChIp), 5mC (MIRA) and 5hmC (hMeDIP) profiles were analyzed in neural progenitor cells (NPC) and neurons by using Nimblegen Mouse ChIP-chip 2.1M Economy Whole-Genome Tiling - 4 Array Set. In order to compare two different techniques of 5hmC profiling, we performed 5hmC profiling with Hydroxymethyl Collector™ Kit (Active Motif) method and hybridized it on mouse Chr7 fragment (Nimblegen). As an independent experiment, 5hmC profiling was performed by using hMeDIP method and hybridized on mouse Chr7 fragment (Nimblegen). After MIRA enrichment and genome amplification, DNA was hybridized on mouse Chr7 fragment (Nimblegen). Analysis of epigenetic changes during neural differentiation due to comparisson of epigenetic patterns in neural progenitor cells versus neurons.
2012-12-31 | E-GEOD-38118 | biostudies-arrayexpress
Project description:A cardinal property of neural stem cells (NSCs) is their ability to adopt multiple fates upon differentiation. The epigenome is widely seen as a read-out of cellular potential and a manifestation of this can be seen in embryonic stem cells (ESCs), where promoters of many lineage-specific regulators are marked by a bivalent epigenetic signature comprising trimethylation of both lysine 4 and lysine 27 of histone H3 (H3K4me3 and H3K27me3, respectively). Bivalency has subsequently emerged as a powerful epigenetic indicator of stem cell potential. Here, we have interrogated the epigenome during differentiation of ESC-derived NSCs to immature GABAergic interneurons. We show that developmental transitions are accompanied by loss of bivalency at many promoters in line with their increasing developmental restriction from pluripotent ESC through multipotent NSC to committed GABAergic interneuron. At the NSC stage, the promoters of genes encoding many transcriptional regulators required for differentiation of multiple neuronal subtypes and neural crest appear to be bivalent, consistent with the broad developmental potential of NSCs. Upon differentiation to GABAergic neurons, all non-GABAergic promoters resolve to H3K27me3 monovalency, whereas GABAergic promoters resolve to H3K4me3 monovalency or retain bivalency. Importantly, many of these epigenetic changes occur prior to any corresponding changes in gene expression. Intriguingly, another group of gene promoters gain bivalency as NSCs differentiate toward neurons, the majority of which are associated with functions connected with maturation and establishment and maintenance of connectivity. These data show that bivalency provides a dynamic epigenetic signature of developmental potential in both NSCs and in early neurons. Neural stem cells derived from mouse embryonic stem cells were differentiated into neurons and FACS purified based on RedStar fluorescence driven by the Tau promoter. Chromatin was prepared from NSCs and neurons (n=1), sonicated to roughly 300bp and immunoprecipitated with antibodies against H3K4me3, H3K27me3, total Histone H3 and total IgG, alongside a 5% input sample. K4/K27 and corresponding input samples were analysed by ChIPSeq
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2011-12-31 | E-GEOD-24131 | biostudies-arrayexpress
Project description:Adult neural progenitor cells (aNPCs) are a potential autologous cell source for cell replacement in neurologic diseases such as Parkinson’s disease or stroke or for cell-based gene therapy for neurometabolic diseases. Easy accessibility, long-term expandability and detailed characterization of NPC properties are important requisites for their future translational/clinical applications. aNPC can be isolated from different regions of the adult human brain including the accessible subcortical white matter (aNPCWM), but systematic studies comparing long-term expanded aNPCWM with aNPC from neurogenic brain regions to check for their NPC characteristics and performance are not available. Freshly isolated cells from subcortical white matter and hippocampus (aNPCHIP) expressed oligodendrocyte progenitor cell (OPC) markers such as A2B5, NG2 and OLIG2 in ~20% of cells but no neural stem cell (NSC) markers such CD133 (Prominin1), NESTIN, SOX2 or PAX6. The EGF receptor (EGFR) protein was expressed in 18% of aNPCWM and 7% of aNPCHIP, but only a small fraction of 1 cell out 694 cells from white matter and only 1 out of 1,331 hippocampal cells were able to generate neurospheres. Studies comparing subcortical aNPCWM with their hippocampal counterparts showed that both NPC types expressed mainly markers of glial origin such as NG2, A2B5 and OLIG2, and the NSC/NPC marker Nestin, but no pericyte markers. Both NPC types were able to produce fully mature neurons, astrocytes and oligodendrocytes in comparable amounts to fetal NSC. Whole transcriptome analyses finally confirmed the strong similarity of aNPCWM with aNPCHIP. Our data show that aNPCWM are multipotent NPC with long-term expandability capacity similar to NPC from hippocampus making them an easily accessible source for possible autologous NPC-based treatment strategies. Isolation and propagation of multipotent NPCs. Adult human hippocampal (hip) and subcortical white matter (wm) tissue was obtained from routine epilepsy surgery procedures following informed consent of the subjects. All procedures were in accordance with the Helsinki convention and approved by the Ethical Committee of the University of Dresden (No. 47032006). All subjects underwent high-resolution magnetic resonance imaging excluding tumors and were screened for the presence of infectious disease. In all cases the neuropathological examinations did not reveal evidences for tumor formation. Gene expression Single-channel oligonucleotide microarray analysis. For the gene expression microarray analysis we used the Affimetrix U133A chips containing 22.215 probe sets representing at least 12.905 individual genes. The whole procedure was performed following the manufacturer’s standard protocol (Affimetrix, Santa Clara, CA). For the data processing, normalization was calculated with the GCRMA (GC content corrected Robust Multi-array Analysis) algorithm.
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