WT vs Hypomethylated Forebrain Gene Expression
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE14216 | GEO | 2009/12/12
SECONDARY ACCESSION(S): PRJNA111343
REPOSITORIES: GEO
Similar Datasets
Project description:DNA methylation is a major epigenetic factor regulating genome reprogramming, cell differentiation, developmental gene expression. To understand the role DNA methylation in CNS neurons, we generated conditional Dnmt1 mutant mice that possess ~90% hypomethylated cortical and hippocampal cells in the dorsal forebrain from E13.5 on. The mutant mice were viable with a normal lifespan, but displayed severe neuronal cell death between E14.5 to 3-weeks postnatally. Accompanied with the striking cortical and hippocampal degeneration, adult mutant mice exhibited neurobehavioral defects in learning and memory in adulthood. Unexpectedly, a fraction of Dnmt1-/- cortical neurons survived through postnatal development, so that the residual cortex in mutant mice contained 20-30% of hypomethylated neurons throughout the life. Hypomethylated excitatory neurons exhibited multiple defects in postnatal maturation including abnormal dendritic arborization and impaired neuronal excitability. The mutant phenotypes are coupled with deregulation of those genes involved in neuronal layer-specification, cell death, and the function of ion channels. Our results suggest that DNA methylation, through its role in modulating neuronal gene expression, plays multiple roles in regulating cell survival, neuronal migration and maturation in the CNS. Experiment Overall Design: We compared gene expression patterns in Wildtype and DNA methylation deficient (Emx1-cre; Dnmt1 mutant) mouse dorsal cortex. We performed 3 replicates using different each individual mouse strain. The Sample GSM350992 table is the average log ratio for the 3 replicatesArrays were performed in triplicate.
2009-12-18 | E-GEOD-14216 | biostudies-arrayexpress
Project description:Two major DNA methylation-catalyzing enzymes, Dnmt1 and Dnmt3a, are expressed in postmitotic neurons, but their function in the adult central nervous system is unclear. We generated conditional mutant mice (CamKIIa Cre; Dnmt loxP) that lack either Dnmt1 or Dnmt3a, or both, exclusively in forebrain excitatory neurons and found only double-knockout (DKO) mice exhibited abnormal hippocampal CA1 long-term plasticity and deficits of learning and memory. DKO neurons also exhibit a significant up-regulation of immune genes, such as class I MHC and Stat1, which are implicated in synaptic plasticity. Four pairs of 2-3 month-old DKO and litter mate control were used. RNA samples were extracted from the cortex and hippocampus for gene expression array analysis.
2010-12-03 | E-GEOD-19367 | biostudies-arrayexpress
Project description:Primary cortical neurons were isolated from E15 mice and after 5 days in vitro were untreated or treated for 24 h with mesenchymal stem cell conditioned medium and then untreated or treated for a further 24 h with NMDA. Neuron gene expression was profiled and compared between the four different conditions (neurons, neurons+MSC cm, neurons+NMDA, neurons+MSC cm+NMDA) to investigate the molecular mechanisms of MSC neuroprotection. Mesenchymal stem cells (MSC) promote functional recovery in experimental models of central nervous system (CNS) pathology and are currently being tested in clinical trials for stroke, multiple sclerosis and CNS injury. Their beneficial effects are attributed to activation of endogenous CNS repair processes and immune regulation but their mechanisms of action are poorly understood. Here we investigated the neuroprotective effects of MSC in simplified MSC-neuron co-culture systems and in mice using models of glutamate excitotoxicity. MSC protected primary cortical neurons against glutamate (NMDA) receptor-induced death and conditioned medium from MSC (MSC cm), but not control NIH3T3 cells, was sufficient for this effect. MSC cm neuroprotection in mouse cortical neurons was reduced by neutralizing antibodies to bFGF and associated with altered gene expression in neurons towards an immature phenotype as well as reduced neuronal Grin1, Grin2a and Grin2b mRNA levels in response to NMDA stimulation. Further, MSC cm neuroprotection in rat retinal ganglion cells was associated with absence of glutamate-induced calcium influx. Adoptive transfer of EGFP+MSC in a mouse kainic acid seizure model reduced CA3 neuron damage and hippocampal astrocytosis and resulted in the increased expression of neuronal genes that are upregulated by MSC cm, Bmi1, Ddx4, Ezh1, in the hippocampus. These results show that MSC mediate direct neuroprotection against glutamate excitotoxicity by secreting bFGF, reducing glutamate receptor expression and function and altering neuron gene expression towards an immature pattern, and provide evidence for a link between the therapeutic effects of MSC and the activation of endogenous repair processes following CNS injury. In vitro cultures primary cortical neurons from mice were protected from glutamate excitotoxicity when pre-treated with MSC cm. Global gene expression changes induced in neurons before and after treatment with MSC cm and/or NMDA were investigated using a cDNA spotted macroarray filter. Four samples were analysed in duplicate: neurons alone (untreated), neurons+MSC cm, neurons+NMDA, neurons+MSC cm+NMDA.
2011-05-01 | E-GEOD-26279 | biostudies-arrayexpress
Project description:Two major DNA methylation-catalyzing enzymes, Dnmt1 and Dnmt3a, are expressed in postmitotic neurons, but their function in the adult central nervous system is unclear. We generated conditional mutant mice (CamKIIa Cre; Dnmt loxP) that lack either Dnmt1 or Dnmt3a, or both, exclusively in forebrain excitatory neurons and found only double-knockout (DKO) mice exhibited abnormal hippocampal CA1 long-term plasticity and deficits of learning and memory. DKO neurons also exhibit a significant up-regulation of immune genes, such as class I MHC and Stat1, which are implicated in synaptic plasticity.
2010-12-03 | GSE19367 | GEO
Project description:Although DNA methylation plays a critical role in the development and function of mammalian central nervous system (CNS), its role in peripheral neurons has not been elucidated. To address this issue, we produced conditional knockout mice (CKO) specifically deleting the gene for maintenance DNA methyltransferase 1 (Dnmt1) during the development of neural crest cells. Despite global hypomethylation in the embryonic dorsal root ganglion (DRG) of the CKO mice, the number of sensory neurons was relatively unaffected. However, expression of many genes required for sensory neuron development was altered in embryonic mutant DRG, including down-regulation of Runx1 and TrkA genes as well as up-regulation of Id1 and Dtx1, two negative regulators for neurogenesis. Accompanied with the downregulation of an NGF receptor TrkA, the peripheral axonal projection and the branching of sensory neurons were impaired. Furthermore, the expression of the neuropeptide Galanin and several vanilloid receptors such as TrpV1 and TrpM8 were not detected in the DRG of the CKO mice during late embryonic and neonatal stages, suggesting that DNA methylation regulates the differentiation program for a subset of nociceptive sensory neurons. Taken together, our findings suggest that through transcriptional regulation of key developmental genes in sensory neurons, DNA methylation play a key role in the control of the axonal projection and fate specification of peripheral sensory neurons. We compared gene expression patterns in Wildtype and DNA methylation deficient (Wnt1-cre; Dnmt1 mutant) mouse dorsal cortex. We performed 4 replicates using different each individual mouse strain. The Sample GSM565172 table is the average log ratio for the 4 replicatesArrays were performed.
2011-12-01 | E-GEOD-23530 | biostudies-arrayexpress
Project description:Autism spectrum disorders (ASD) represent neurodevelopmental disorders characterized by social deficits, repetitive behaviors, and various comorbidities, including epilepsy. ANK2, which encodes a neuronal scaffolding protein, is frequently mutated in ASD, but its in vivo functions and disease-related mechanisms are largely unknown. Here, we report that mice with Ank2 knockout restricted to cortical and hippocampal excitatory neurons (Ank2-cKO mice) show ASD-related behavioral abnormalities and juvenile seizure-related death. Ank2-cKO cortical neurons show abnormally increased excitability and firing rate. These changes accompanied decreases in the total level and function of the Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels and the density of these channels in the enlengthened axon initial segment. Importantly, the Kv7 agonist, retigabine, rescued neuronal excitability, juvenile seizure-related death, and hyperactivity in Ank2-cKO mice. These results suggest that Ank2 regulates neuronal excitability by regulating the length of and Kv7 density in the AIS and that Kv7 channelopathy is involved in Ank2-related brain dysfunctions.
2023-07-20 | PXD041769 | Pride
Project description:Autism spectrum disorders (ASD) represent neurodevelopmental disorders characterized by social deficits, repetitive behaviors, and various comorbidities, including epilepsy. ANK2, which encodes a neuronal scaffolding protein, is frequently mutated in ASD, but its in vivo functions and disease-related mechanisms are largely unknown. Here, we report that mice with Ank2 knockout restricted to cortical and hippocampal excitatory neurons (Ank2-cKO mice) show ASD-related behavioral abnormalities and juvenile seizure-related death. Ank2-cKO cortical neurons show abnormally increased excitability and firing rate. These changes accompanied decreases in the total level and function of the Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels and the density of these channels in the enlengthened axon initial segment. Importantly, the Kv7 agonist, retigabine, rescued neuronal excitability, juvenile seizure-related death, and hyperactivity in Ank2-cKO mice. These results suggest that Ank2 regulates neuronal excitability by regulating the length of and Kv7 density in the AIS and that Kv7 channelopathy is involved in Ank2-related brain dysfunctions.
2023-03-19 | MSV000091510 | MassIVE
Project description:Post-mitotic neurons exhibit DNA methylation changes, contrary to the longstanding belief that the epigenetic pattern in terminally differentiated cells is essentially unchanging. While the mechanism and physiological significance of DNA demethylation in neurons have been extensively elucidated, occurrence of de novo DNA methylation and its impacts have been much less investigated. Here we show that neuronal activation induces global de novo DNA methylation at enhancer regions that can repress target genes in primary cultured hippocampal neurons. The functional significance of this de novo DNA methylation was underpinned by the demonstration that inhibition of DNA methyltransferase (DNMT) activity decreased neuronal activity-induced excitatory synaptogenesis. Overexpression of WW and C2 Domain containing 1 (Wwc1), a representative target gene of de novo DNA methylation, could phenocopy this DNMT inhibition-induced decrease in the synaptogenesis. We found that both DNMT1 and DNMT3a were required for the neuronal activity-induced de novo DNA methylation of Wwc1 enhancer. Taking these findings altogether, we concluded that activity-induced de novo DNA methylation affecting gene expression has impacts on neuronal physiology comparable to those of DNA demethylation.
2020-04-26 | GSE149342 | GEO
Project description:In this study, we analyzed global gene expressions of colon tumors from DNA hypomethylated and the control mice. We found that DNA hypomethylated tumors express significantly higher levels of intestinal differentiation-related genes when compared with the control tumors. These results suggest that DNA methylation may play a role in the maintenance of undifferentiated state of colon tumor cells. Two different Dnmt1 mutant alleles were used in this study; hypomorphic Dnmt1chip allele and conventional KO Dnmt1c allele, which described previously. Previous studies indicated that Dnmt1chip/c mice have reduced DNA methylation contents at pericentromeric satellite repeats, while Dnmt1chip/+ mice have the same levels of genomic methylation as wildtype mice. Experimental mice in an isogenic F1 hybrid background were obtained by breeding Dnmt1c/+; ApcMin/+ mouse in the C57BL/6 background with Dnmt1chip/chip; Apc+/+ mouse in the 129Sv4 background. Six-week-old DNA hypomethylated (Dnmt1chip/c; ApcMin/+) and the control (Dnmt1chip/+; ApcMin/+) mice were fed with 2% (w/v) dextran sodium sulfate (DSS), a potent promoter for colon carcinogenesis. At 20 weeks of age, colon tumors were harvested from both cohorts (n=3 for both DNA hypomethylated tumors and the control tumors) and analyzed for their gene expressions.
2015-08-05 | E-GEOD-60620 | biostudies-arrayexpress
Project description:We present high quality deep read-depth single cell RNA sequencing for 91 cells from five mouse tissues and 18 cells from two rat tissues, along with 30 control samples of bulk RNA diluted to single-cell levels. We find that transcriptomes differ globally across tissues with regard to the number of genes expressed, the average expression patterns, and within cell-type variation patterns. We develop methods to filter genes for reliable quantification and to calibrate biological variation. All cell types include genes with high variability in expression, in a tissue-specific manner. We also find evidence that single cell variability of neuronal genes in mice is correlated with that in rats consistent with the hypothesis that levels of variation may be conserved. From an initial 143 cells we identified 107 high quality samples with deep genic coverage, including 13 brown adipocytes, 19 cardiomyocytes, 19 cortical pyramidal neurons and 18 hippocampal pyramidal neurons from embryonic mouse, 8 cortical pyramidal neurons and 8 hippocampal pyramidal neurons from embryonic rat, and 22 serotonergic neurons from adult mouse. While mouse data is collected from three strains of mice at different ages, each cell type dataset is internally consistent. There are no technical replicates of single-cell samples. We additionally prepared 30 control samples, amplifications of bulk total cardiomyocyte RNA diluted to single cell quantities.
2015-05-21 | E-GEOD-56638 | biostudies-arrayexpress