Overexpression of Gadd45b perturbs DNA methylation in mouse dopaminergic neurons
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PROVIDER: PRJNA736683 | ENA |
REPOSITORIES: ENA
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Project description:Age is a major risk factor for neurodegenerative diseases like Parkinson disease, but few studies have explored the contribution of key hallmarks of aging, namely DNA methylation changes and heterochromatin destructuration, in the neurodegenerative process. Here, we investigated the consequences of viral overexpression of Gadd45b, a multifactorial protein involved in DNA demethylation, in the mouse midbrain. Gadd45b overexpression induced global and stable changes in DNA methylation, particularly in introns of genes related to neuronal functions, as well as on LINE-1 transposable elements. This was paralleled by disorganized heterochromatin, increased DNA damage and vulnerability to oxidative stress. LINE-1 de-repression, a potential source of DNA damage, preceded Gadd45b-induced neurodegeneration, whereas prolonged Gadd45b expression deregulated expression of genes related to heterochromatin maintenance, DNA methylation or Parkinson disease. Our data indicates that aging-related alterations contribute to dopaminergic neuron degeneration with potential implications for Parkinson disease.
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Project description:Dopaminergic neurons located in the ventral midbrain can be broadly subdivided into two distinct subpopulations. Substantia nigra (SN) dopaminergic neurons are highly sensitive to toxic insults and selectively degenerate in Parkinson’s disease, while ventral tegmental area (VTA) dopaminergic neurons are associated with other neurological disorders. Access to enriched cultures of SN and VTA dopaminergic neuronal subpopulations will facilitate disease modelling and give insight in the differential vulnerability, but it is unclear how the differentiation of human ES cells can be directed towards these distinct lineages. We found that overexpression of the lineage specifying transcription factors Sox6 and Otx2 can direct the differentiation of human ES cells into enriched populations of respectively SN or VTA neurons. Proteomic analysis of these cultures resulted in the identification of several differential expressed proteins and provided insight in pathways contributing to the selective vulnerability of SN.
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Project description:Identification of new small molecules that regulate the step-wise differentiation of hPSC into dopaminergic neurons population. Furthermore, the naturally occurring steroid, guggulsterone, was found to be the most effective inducer of neural stem cells into dopaminergic neurons. Total RNA extracted at different stages of neural differentiation from human pluripotent stem cells
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Project description:The transcription factor Fer2 plays a neuroprotective role in the dopaminergic neurons of the fly brain, but the underlying molecular mechanisms are not understood. By performing RNA-seq on isolated dopaminergic PAM neurons after Fer2 constitutive overexpression, we identified over one hundred genes differentially regulated in response to PAM-specific Fer2 overexpression.
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Project description:Engrailed homeoproteins are expressed in adult dopaminergic neurons of the substantia nigra. In Engrailed1 heterozygous mice, these neurons start dying at 6 weeks, are more sensitive to oxidative stress and progressively develop traits similar to those observed following an acute and strong oxidative stress inflected to wild-type neurons. These changes include DNA strand breaks and the modification (intensity and distribution) of several nuclear and nucleolar heterochromatin marks. Engrailed1 and Engrailed2 are biochemically equivalent transducing proteins previously used to antagonize dopaminergic neuron death in Engrailed heterozygous mice and in mouse models of Parkinson disease. Accordingly, we show that, following an acute oxidative stress, a single Engrailed2 injection restores all nuclear and nucleolar heterochromatin marks, decreases the number of DNA strand breaks and protects dopaminergic neurons against apoptosis. RNA-seq data for differentially expressed genes in the SNpc of En1+/- mice, En2 infused mice and 6-OHDA/En2 injection experiments.
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Project description:RNA-SEQ profiling of mouse whole midbrain and dopaminergic neurons from the mouse mid-brain Murine whole midbrain and murine midbrain dopaminergic neurons
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Project description:Identification of new small molecules that regulate the step-wise differentiation of hPSC into dopaminergic neurons population. Furthermore, the naturally occurring steroid, guggulsterone, was found to be the most effective inducer of neural stem cells into dopaminergic neurons.
2013-04-24 | GSE42265 | GEO
Project description:modENCODE_submission_467 This submission comes from a modENCODE project of Robert Waterston. For full list of modENCODE projects, see http://www.genome.gov/26524648 Project Goal: Our experiments are designed to detect all C. elegans transcripts by hybridizing RNA to commerically available genome tiling arrays. To maximize the chances of detecting rare transcripts with limited expression in specific cells, we are extracting RNA from selected embryonic cells isolated by FACS and from postembryonic cells by use of the mRNA tagging method. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf Keywords: Transcript tiling array analysis EXPERIMENT TYPE: Transcript tiling array analysis. BIOLOGICAL SOURCE: Strain: BY200 (engineered, target gene dat-1 tagged by GFP); Tissue: dopaminergic neurons (embryonic); Developmental Stage: Mixed stage of embryos 20dC; Genotype: dat-1::GFP (pRN2003); Sex: Hermaphrodite; NUMBER OF REPLICATES: 3; EXPERIMENTAL FACTORS: Strain BY200 (engineered, target gene dat-1 tagged by GFP); temperature 20; Developmental Stage Mixed stage of embryos 20dC; Tissue dopaminergic neurons (embryonic)
2010-08-04 | E-GEOD-23257 | biostudies-arrayexpress