Neuronal and glial DNA methylation and gene expression changes in early epileptogenesis
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ABSTRACT:
PROVIDER: PRJNA574618 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10194900.fastq.gz | Fastqsanger.gz | |||
| SRR10194901.fastq.gz | Fastqsanger.gz | |||
| SRR10194902.fastq.gz | Fastqsanger.gz | |||
| SRR10194903.fastq.gz | Fastqsanger.gz | |||
| SRR10194904.fastq.gz | Fastqsanger.gz |
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Project description:Mesial Temporal Lobe Epilepsy is characterized by progressive changes of both neurons and glia, also referred to as epileptogenesis. No curative treatment options, apart from surgery, are available. DNA methylation (DNAm) is a potential upstream mechanism in epileptogenesis and may serve as a novel therapeutic target. To our knowledge, this is the first study to investigate epilepsy-related DNAm, gene expression (GE) and their relationship, in neurons and glia. We used the intracortical kainic acid injection model to elicit status epilepticus. At 24 hours post injection, hippocampi from eight kainic acid- (KA) and eight saline-injected (SH) mice were extracted and shock frozen. Separation into neurons and glial nuclei was performed by flow cytometry. Changes in DNAm and gene expression were measured with reduced representation bisulfite sequencing (RRBS) and mRNA-sequencing (mRNAseq). Statistical analyses were performed in R with the edgeR package. We observed fulminant DNAm- and GE changes in both neurons and glia at 24 hours after initiation of status epilepticus. The vast majority of these changes were specific for either neurons or glia. At several epilepsy-related genes, like HDAC11, SPP1, GAL, DRD1 and SV2C, significant differential methylation and differential gene expression coincided. We found neuron- and glia-specific changes in DNAm and gene expression in early epileptogenesis. We detected single genetic loci in several epilepsy-related genes, where DNAm and GE changes coincide, worth further investigation. Further, our results may serve as an information source for neuronal and glial alterations in both DNAm and GE in early epileptogenesis.
2019-12-06 | GSE138100 | GEO
Project description:BACKGROUND AND AIMS:Mesial Temporal Lobe Epilepsy is characterized by progressive changes of both neurons and glia, also referred to as epileptogenesis. No curative treatment options, apart from surgery, are available. DNA methylation (DNAm) is a potential upstream mechanism in epileptogenesis and may serve as a novel therapeutic target. To our knowledge, this is the first study to investigate epilepsy-related DNAm, gene expression (GE) and their relationship, in neurons and glia. METHODS:We used the intracortical kainic acid injection model to elicit status epilepticus. At 24 hours post injection, hippocampi from eight kainic acid- (KA) and eight saline-injected (SH) mice were extracted and shock frozen. Separation into neurons and glial nuclei was performed by flow cytometry. Changes in DNAm and gene expression were measured with reduced representation bisulfite sequencing (RRBS) and mRNA-sequencing (mRNAseq). Statistical analyses were performed in R with the edgeR package. RESULTS:We observed fulminant DNAm- and GE changes in both neurons and glia at 24 hours after initiation of status epilepticus. The vast majority of these changes were specific for either neurons or glia. At several epilepsy-related genes, like HDAC11, SPP1, GAL, DRD1 and SV2C, significant differential methylation and differential gene expression coincided. CONCLUSION:We found neuron- and glia-specific changes in DNAm and gene expression in early epileptogenesis. We detected single genetic loci in several epilepsy-related genes, where DNAm and GE changes coincide, worth further investigation. Further, our results may serve as an information source for neuronal and glial alterations in both DNAm and GE in early epileptogenesis.
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Project description:Morphological changes in mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis (mTLE-HS) are well characterized. Yet it remains elusive whether these are a consequence of seizures or originate from a hitherto unknown underlying pathology. We recently published data on changes in gene expression (GE) and DNA methylation (DNAm) in the ipsilateral hippocampus (ILH), using the intracortical kainate mouse model of mTLE-HS. In order to explore the effects of epileptic activity alone and also to further disentangle what triggers morphological alterations, we investigated glial and neuronal changes in GE and DNAm in the contralateral hippocampus (CLH). The intracortical kainic acid mouse model of mTLE-HS was used to elicit status epilepticus. Hippocampi contralateral to injection site from 8 kainate injected (KA) and 8 sham (SH) mice were extracted, and shock frozen at 24 hours post injection. Glial- and neuronal nuclei were sorted by flow cytometry. Alterations in GE and DNAm were assessed using reduced representation bisulfite sequencing (RRBS) and RNA sequencing (RNAseq). The R package edgeR was used for statistical analysis. The CLH featured substantial, mostly cell-specific changes in both GE and DNAm in glia and neurons. While changes in GE overlapped to a great degree between CLH and ILH, alterations in DNAm did not. In the CLH we found a significantly lower number of glial genes up- and downregulated compared to previous results from the ILH. Furthermore, several genes and pathways potentially involved in anti-epileptogenic effects were upregulated in the CLH. By comparing GE data from the CLH to previous results from the ILH (featuring hippocampal sclerosis), we derive potential upstream targets for epileptogenesis, including glial Cox2 and Cxcl10. Despite the absence of morphological changes, the CLH displays substantial changes in GE and DNAm. We find that GE changes related to potential anti-epileptogenic effects seem to dominate compared to pro-epileptogenic effects in the CLH and speculate whether this imbalance contributes to prevent morphological alterations like neuronal death and reactive gliosis.
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Project description:We applied Illumina Human Methylation450K array to perform a genomic-scale single-site resolution DNA methylation analysis in neuronal and nonneuronal (primarily glial) nuclei separated from the orbitofrontal cortex of postmortem human brain. The findings were validated using enhanced reduced representation bisulfite sequencing. We identified thousands of sites differentially methylated (DM) between neuronal and nonneuronal cells. The DM sites were depleted within CpG island–containing promoters but enriched in predicted enhancers. Classification of the DM sites into those undermethylated in neurons (neuronal type) and those undermethylated in nonneuronal cells (glial type), combined with findings of others that methylation within control elements typically negatively correlates with gene expression, yielded large sets of predicted neuron-specific and non– neuron-specific genes. These sets of predicted genes were in excellent agreement with the available direct measurements of gene expression in human and mouse. We also found a distinct set of DNA methylation patterns that were unique for neuronal cells. In particular, neuronal-type differential methylation was overrepresented in CpG island shores, enriched within gene bodies but not in intergenic regions, and preferentially harbored binding motifs for a distinct set of transcription factors, including neuron-specific activity-dependent factors. Finally, non-CpG methylation was substantially more prevalent in neurons than in nonneuronal cells. Genomic DNA was isolated from FACS-sorted human brain neuronal and nonneuronal nuclei. DNA was bisulfite converted and hybridised to the Illumina Infinium 450K Human Methylation Beadchip array. Six subjects in two technical replicate expriments were analyzed.
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Project description:We report early mechanisms of epileptogenesis in a zebrafish model of Dravet syndrome caused by missense mutation in scn1lab gene.
2020-02-25 | GSE145801 | GEO
Project description:The purpose of this experiment was to identify oestrogen regulated genes in human primary cell cultures of neuronal and glial cells modelling the developing human nervous system. We were especially interested in genes involved in proliferation, differentiation and migration of neuronal cells and genes involved in or linked to neurodegenerative diseases. We have therefore assessed gene expression changes, using Affymetrix GeneChips (HG-U133A), of oestrogen treated human neuronal/ glial cell cultures. We continued with 14 selected genes and confirmed the gene expression changes, by relative quantitative real time PCR, of 6 genes (p< 0.05) important in neuronal development, three of which also are suggested to have links to neurodegenerative diseases. Experiment Overall Design: Primary mixed neuronal/glial cell cultures were established from human brain tissue, which was obtained from 8-12 weeks old fetuses at legal abortion after informed consent from the patients. Procedures were approved by the local Ethics committee at the Karolinska University Hospital, Stockholm. A total of 23 tissue samples yielding 9 cell cultures were used in this experiment. Half of the cell cultures were treated with 2µM β-oestradiol the day after seeding. The duration of the oestrogen treatment was 7 days and the cells were harvested after 8 days of culturing for RNA extraction. Extracted RNA from untreated respectively oestrogen treated cell cultures were pooled yileding two samples, which were each hybridised to Affymetrix microarrys. In this study oestrogen treatment of human neuronal/glial cell cultures was found to regulate 6 genes important in the development of the nervous system.
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2016-01-06 | E-GEOD-76547 | biostudies-arrayexpress
Project description:Neuronal or glial cell fates related gene expression from single cells with variety of sAPPa or total Aβ secretion profiles were presented here. Single living human iPSC-derived forebrain neuronal cells with variety of sAPPa or total Aβ secretion profiles were selected and examined for gene expression.
2016-01-06 | E-GEOD-76545 | biostudies-arrayexpress
Project description:Intestinal ganglionic cells in the adult enteric nervous system (ENS) are continually exposed to stimuli from the surrounding microenvironment, and need at times to respond to disturbed homeostasis following acute intestinal injury. The kinase DCLK1 and intestinal Dclk1-positive cells have been reported to contribute to intestinal regeneration. While Dclk1-positive cells are present in adult enteric ganglia, their cellular identity and response to acute injury have not been investigated in detail. Here, we reveal the presence of distinct Dclk1-tdTom+/CD49b+ glial-like and Dclk1-tdTom+/CD49b- neuronal cell types in adult myenteric ganglia. These ganglionic cells demonstrate distinct patterns of tracing over time, yet show a similar expansion in response to elevated serotonergic signaling. Interestingly, Dclk1-tdTom+ glial-like and neuronal cell types appear resistant to acute irradiation injury-mediated cell death. Moreover, Dclk1-tdTom+/CD49b+ glial-like cells show prominent changes in gene expression profiles induced by injury, in contrast to Dclk1-tdTom+/CD49b- neuronal cell types. Finally, subsets of Dclk1-tdTom+/CD49b+ glial-like cells demonstrate prominent overlap with Nestin and p75NTR, and strong responses to elevated serotonergic signaling or acute injury. These findings, together with their role in early development and their neural-crest like gene expression signature, suggest the presence of reserve progenitor cells in the adult Dclk1 glial cell lineage.
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