REST and Neural Gene Network Dysregulation in iPS Cell Models of Alzheimer’s Disease (Affymetrix NPC data set)
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PROVIDER: PRJNA482603 | ENA |
REPOSITORIES: ENA
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Project description:Alzheimer’s disease (AD) is preceded by a long prodromal period of decades during which pathology accumulates in the brain prior to the onset of dementia. The molecular basis of these changes as well as how and when they start are unclear. Here we have analyzed neural progenitor (NP) cells and neurons generated from induced pluripotent stem cells (iPSCs) from individuals with sporadic AD (AD) and age-matched controls. Transcriptome analysis does not distinguish between iPSCs from individuals with SAD and age-matched controls, but shows major differences in iPSC-derived NP cells and neurons in gene networks related to neuronal differentiation, neurogenesis and synaptic transmission. SAD NP cells exhibit accelerated neuronal differentiation, leading to the generation of neurons with increased synapse formation and electrical excitability. Network analysis of the transcriptome implicates the transcriptional repressor REST/NRSF and two components of the polycomb repressive complex 2, SUZ12 and EZH2. Accelerated differentiation of SAD NP cells was reversed by exogenous REST expression and mimicked in normal NP cells by REST knockdown. The phenotype of accelerated neural differentiation was recapitulated in NP cells and cerebral organoids derived from gene-edited iPSC lines that express apolipoprotein E4 (APOE4), the major genetic risk factor for AD. Network analysis of the APOE4-related transcriptome again showed reduced function of REST, EZH2 and SUZ12 to be the major predicted regulatory changes. Reduced function of the REST repressor was due to reduced nuclear translocation and chromatin binding, and was associated with disruption of the nuclear membrane and lamina in SAD and APOE4 NP cells. Thus, impaired function of specific transcription factors and changes in nuclear architecture may be among the earliest events in the pathogenesis of AD.
2019-01-29 | GSE117586 | GEO
Project description:Alzheimer’s disease (AD) is preceded by a long prodromal period of decades during which pathology accumulates in the brain prior to the onset of dementia. The molecular basis of these changes as well as how and when they start are unclear. Here we have analyzed neural progenitor (NP) cells and neurons generated from induced pluripotent stem cells (iPSCs) from individuals with sporadic AD (AD) and age-matched controls. Transcriptome analysis does not distinguish between iPSCs from individuals with SAD and age-matched controls, but shows major differences in iPSC-derived NP cells and neurons in gene networks related to neuronal differentiation, neurogenesis and synaptic transmission. SAD NP cells exhibit accelerated neuronal differentiation, leading to the generation of neurons with increased synapse formation and electrical excitability. Network analysis of the transcriptome implicates the transcriptional repressor REST/NRSF and two components of the polycomb repressive complex 2, SUZ12 and EZH2. Accelerated differentiation of SAD NP cells was reversed by exogenous REST expression and mimicked in normal NP cells by REST knockdown. The phenotype of accelerated neural differentiation was recapitulated in NP cells and cerebral organoids derived from gene-edited iPSC lines that express apolipoprotein E4 (APOE4), the major genetic risk factor for AD. Network analysis of the APOE4-related transcriptome again showed reduced function of REST, EZH2 and SUZ12 to be the major predicted regulatory changes. Reduced function of the REST repressor was due to reduced nuclear translocation and chromatin binding, and was associated with disruption of the nuclear membrane and lamina in SAD and APOE4 NP cells. Thus, impaired function of specific transcription factors and changes in nuclear architecture may be among the earliest events in the pathogenesis of AD.
2019-01-29 | GSE117585 | GEO
Project description:Alzheimer’s disease (AD) is preceded by a long prodromal period of decades during which pathology accumulates in the brain prior to the onset of dementia. The molecular basis of these changes as well as how and when they start are unclear. Here we have analyzed neural progenitor (NP) cells and neurons generated from induced pluripotent stem cells (iPSCs) from individuals with sporadic AD (AD) and age-matched controls. Transcriptome analysis does not distinguish between iPSCs from individuals with SAD and age-matched controls, but shows major differences in iPSC-derived NP cells and neurons in gene networks related to neuronal differentiation, neurogenesis and synaptic transmission. SAD NP cells exhibit accelerated neuronal differentiation, leading to the generation of neurons with increased synapse formation and electrical excitability. Network analysis of the transcriptome implicates the transcriptional repressor REST/NRSF and two components of the polycomb repressive complex 2, SUZ12 and EZH2. Accelerated differentiation of SAD NP cells was reversed by exogenous REST expression and mimicked in normal NP cells by REST knockdown. The phenotype of accelerated neural differentiation was recapitulated in NP cells and cerebral organoids derived from gene-edited iPSC lines that express apolipoprotein E4 (APOE4), the major genetic risk factor for AD. Network analysis of the APOE4-related transcriptome again showed reduced function of REST, EZH2 and SUZ12 to be the major predicted regulatory changes. Reduced function of the REST repressor was due to reduced nuclear translocation and chromatin binding, and was associated with disruption of the nuclear membrane and lamina in SAD and APOE4 NP cells. Thus, impaired function of specific transcription factors and changes in nuclear architecture may be among the earliest events in the pathogenesis of AD.
2019-01-29 | GSE117584 | GEO
Project description:REST and Neural Gene Network Dysregulation in iPS Cell Models of Alzheimer’s Disease (Affymetrix neurons data set)
| PRJNA482600 | ENA
Project description:REST and Neural Gene Network Dysregulation in iPS Cell Models of Alzheimer’s Disease (Affymetrix iPSC data set)
| PRJNA482599 | ENA
Project description:REST and Neural Gene Network Dysregulation in iPS Cell Models of Alzheimer’s Disease
| PRJNA482597 | ENA
Project description:Alzheimer’s disease (AD) is preceded by a long prodromal period of decades during which pathology accumulates in the brain prior to the onset of dementia. The molecular basis of these changes as well as how and when they start are unclear. Here we have analyzed neural progenitor (NP) cells and neurons generated from induced pluripotent stem cells (iPSCs) from individuals with sporadic AD (AD) and age-matched controls. Transcriptome analysis does not distinguish between iPSCs from individuals with SAD and age-matched controls, but shows major differences in iPSC-derived NP cells and neurons in gene networks related to neuronal differentiation, neurogenesis and synaptic transmission. SAD NP cells exhibit accelerated neuronal differentiation, leading to the generation of neurons with increased synapse formation and electrical excitability. Network analysis of the transcriptome implicates the transcriptional repressor REST/NRSF and two components of the polycomb repressive complex 2, SUZ12 and EZH2. Accelerated differentiation of SAD NP cells was reversed by exogenous REST expression and mimicked in normal NP cells by REST knockdown. The phenotype of accelerated neural differentiation was recapitulated in NP cells and cerebral organoids derived from gene-edited iPSC lines that express apolipoprotein E4 (APOE4), the major genetic risk factor for AD. Network analysis of the APOE4-related transcriptome again showed reduced function of REST, EZH2 and SUZ12 to be the major predicted regulatory changes. Reduced function of the REST repressor was due to reduced nuclear translocation and chromatin binding, and was associated with disruption of the nuclear membrane and lamina in SAD and APOE4 NP cells. Thus, impaired function of specific transcription factors and changes in nuclear architecture may be among the earliest events in the pathogenesis of AD.
2019-01-29 | GSE117588 | GEO
Project description:REST and Neural Gene Network Dysregulation in iPS Cell Models of Alzheimer’s Disease (RNA-seq data set)
| PRJNA482601 | ENA
Project description:We profiled REST targets in WT mice, as well as the Alzheimer’s disease 3xTg mouse model, to gain insight into the regulation of physiological pathways by REST, as well as the altered REST cistrome in Alzheimer’s disease.
2022-01-29 | GSE195446 | GEO
Project description:We report the application of MNase-seq (Kent, Adams et al. 2011) to construct genome-wide nucleosome maps from human cells. To date, genome-wide changes in chromatin structure that occur during development in human cells have not been investigated widely. We have constructed and compared genome-wide chromatin maps from undifferentiated human iPS cells and and iPS cells differentiated to neural progenitor cells (NPC).
2019-04-24 | GSE117870 | GEO