Cell-specific Studies Through Novel Mouse Model Reveal the Transcriptomic Response of Retinal Müller Glia to Acute and Chronic Stress [INTACT]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA810711 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18150776_1.fastq.gz | Fastqsanger.gz | |||
| SRR18150776_2.fastq.gz | Fastqsanger.gz | |||
| SRR18150777_1.fastq.gz | Fastqsanger.gz | |||
| SRR18150777_2.fastq.gz | Fastqsanger.gz | |||
| SRR18150778_1.fastq.gz | Fastqsanger.gz |
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Project description:Non-mammalian vertebrates have a robust ability to regenerate injured retinal neurons from Müller glia cells (MG) that activate the proneural factor Achaete-scute homolog 1 (Ascl1/Mash1) and de-differentiate into progenitors cells. In contrast, mammalian MG have a limited regenerative response and fail to upregulate Ascl1 after injury. To test whether Ascl1 could restore a neurogenic potential to mammalian MG, we over-expressed Ascl1 in dissociated mouse MG cultures and intact retinal explants. Ascl1-infected MG upregulate retinal progenitor-specific genes, while downregulating glial genes. Furthermore, Ascl1 remodeled the chromatin at its targets from a repressive to active configuration. MG-derived progenitors differentiated into cells that exhibited neuronal morphologies, expressed retinal subtype-specific neuronal markers, and displayed neuron-like physiological responses. These results indicate that a single transcription factor, Ascl1, can produce a neurogenic state in mature Muller glia. Expresssion profiling was used to determine the genes that were changed after Ascl1 infection of P12 cultured Müller glia compared with those present in P0 progenitors and P7-P21 Müller glia Retinas were dissociated and FAC-sorted from Hes5-GFP mice at P0, P7, P10, P14 or P21 and submitted for profiling. WT Retinas were dissociated at P12, grown for 1 week in culture, and infected with lentiviruses expressing Ascl1 or GFP for four days. Total RNA was extracted and submitted for profiling.
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Project description:Epigenetic regulation of the genome through DNA modifications, mainly methylcytosine (mC) and hydroxymethylcytosine (hmC), alters DNA accessibility, genomic organization and gene expression and is thought to be altered during neurodegenerative diseases, such as age-related macular degeneration (AMD). Analysis of retina epigenetic and transcriptomic signatures at the cell-type specific level is crucial to understanding the pathophysiology of retinal degeneration. We have discovered that Aldh1l1 is specifically expressed in the major macroglia of the retina, the Müller glia, and, unlike the brain, is not expressed in retinal astrocytes. This allows a novel model to study paired epigenetic and transcriptomic signatures in Müller glia using Nuclear Tagging and Translating Ribosome Affinity Purification (NuTRAP) for temporally controlled labeling and isolation of Müller glial DNA and RNA. As validated through a variety of approaches, the Aldh1l1cre/ERT2-NuTRAP model provides Müller glia specific translatome and epigenome profiles. Application of this approach to models of acute injury (optic nerve crush) and chronic stress (aging) uncovered common Müller glia-specific transcriptome changes in inflammatory pathways, as well as differential signatures for each stimulus. The expression of components of the IL1b signalling axis, complement system, and markers of gliosis was enhanced in Müller glia in response to optic nerve crush but not in response to aging. The expression of components of the purinergic receptor and focal adhesion signalling pathways changed uniquely in response to aging but not with optic nerve crush. The Aldh1l1cre/ERT2-NuTRAP model allows focusing molecular analyses to a single, minority cell type within the retina, providing more substantial effect sizes than whole tissue analyses. The NuTRAP model, nucleic acid isolation, and validation approaches presented here can be applied to any retina cell type for which a cell type-specific cre is available.
2022-11-15 | GSE197503 | GEO
Project description:Non-mammalian vertebrates have a robust ability to regenerate injured retinal neurons from Müller glia cells (MG) that activate the proneural factor Achaete-scute homolog 1 (Ascl1/Mash1) and de-differentiate into progenitors cells. In contrast, mammalian MG have a limited regenerative response and fail to upregulate Ascl1 after injury. To test whether Ascl1 could restore a neurogenic potential to mammalian MG, we over-expressed Ascl1 in dissociated mouse MG cultures and intact retinal explants. Ascl1-infected MG upregulate retinal progenitor-specific genes, while downregulating glial genes. Furthermore, Ascl1 remodeled the chromatin at its targets from a repressive to active configuration. MG-derived progenitors differentiated into cells that exhibited neuronal morphologies, expressed retinal subtype-specific neuronal markers, and displayed neuron-like physiological responses. These results indicate that a single transcription factor, Ascl1, can produce a neurogenic state in mature Muller glia. Expresssion profiling was used to determine the genes that were changed after Ascl1 infection of P12 cultured Müller glia compared with those present in P0 progenitors and P7-P21 Müller glia
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Project description:Müller glia play very important and diverse roles in retinal homeostasis and disease, bur very little is known of their development during human retinal embryogenesis. Since they share several markers with retinal progenitors, they are often considered as a different cell population. In this study we isolated CD29+/CD44+cells from retinal organoids formed by hEPSC cells in vitro, and examined their transcriptome profile at various stages of organoid development to identify their transcriptomic profile.
2023-02-21 | E-MTAB-12467 | biostudies-arrayexpress
Project description:Epigenetic regulation of the genome through DNA modifications, mainly methylcytosine (mC) and hydroxymethylcytosine (hmC), alters DNA accessibility, genomic organization and gene expression and is thought to be altered during neurodegenerative diseases, such as age-related macular degeneration (AMD). Analysis of retina epigenetic and transcriptomic signatures at the cell-type specific level is crucial to understanding the pathophysiology of retinal degeneration. We have discovered that Aldh1l1 is specifically expressed in the major macroglia of the retina, the Müller glia, and, unlike the brain, is not expressed in retinal astrocytes. This allows a novel model to study paired epigenetic and transcriptomic signatures in Müller glia using Nuclear Tagging and Translating Ribosome Affinity Purification (NuTRAP) for temporally controlled labeling and isolation of Müller glial DNA and RNA. As validated through a variety of approaches, the Aldh1l1cre/ERT2-NuTRAP model provides Müller glia specific translatome and epigenome profiles. Application of this approach to models of acute injury (optic nerve crush) and chronic stress (aging) uncovered common Müller glia-specific transcriptome changes in inflammatory pathways, as well as differential signatures for each stimulus. The expression of components of the IL1b signalling axis, complement system, and markers of gliosis was enhanced in Müller glia in response to optic nerve crush but not in response to aging. The expression of components of the purinergic receptor and focal adhesion signalling pathways changed uniquely in response to aging but not with optic nerve crush. The Aldh1l1cre/ERT2-NuTRAP model allows focusing molecular analyses to a single, minority cell type within the retina, providing more substantial effect sizes than whole tissue analyses. The NuTRAP model, nucleic acid isolation, and validation approaches presented here can be applied to any retina cell type for which a cell type-specific cre is available.
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Project description:Epigenetic regulation of the genome through DNA modifications, mainly methylcytosine (mC) and hydroxymethylcytosine (hmC), alters DNA accessibility, genomic organization and gene expression and is thought to be altered during neurodegenerative diseases, such as age-related macular degeneration (AMD). Analysis of retina epigenetic and transcriptomic signatures at the cell-type specific level is crucial to understanding the pathophysiology of retinal degeneration. We have discovered that Aldh1l1 is specifically expressed in the major macroglia of the retina, the Müller glia, and, unlike the brain, is not expressed in retinal astrocytes. This allows a novel model to study paired epigenetic and transcriptomic signatures in Müller glia using Nuclear Tagging and Translating Ribosome Affinity Purification (NuTRAP) for temporally controlled labeling and isolation of Müller glial DNA and RNA. As validated through a variety of approaches, the Aldh1l1cre/ERT2-NuTRAP model provides Müller glia specific translatome and epigenome profiles. Application of this approach to models of acute injury (optic nerve crush) and chronic stress (aging) uncovered common Müller glia-specific transcriptome changes in inflammatory pathways, as well as differential signatures for each stimulus. The expression of components of the IL1b signalling axis, complement system, and markers of gliosis was enhanced in Müller glia in response to optic nerve crush but not in response to aging. The expression of components of the purinergic receptor and focal adhesion signalling pathways changed uniquely in response to aging but not with optic nerve crush. The Aldh1l1cre/ERT2-NuTRAP model allows focusing molecular analyses to a single, minority cell type within the retina, providing more substantial effect sizes than whole tissue analyses. The NuTRAP model, nucleic acid isolation, and validation approaches presented here can be applied to any retina cell type for which a cell type-specific cre is available.
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2019-07-23 | GSE122301 | GEO
Project description:Premature infants require oxygen supplementation to survive, but excess oxygen causes retinovascular growth suppression that underlies the leading cause of infant blindness known as retinopathy of prematurity (ROP). We analyzed changes in intermediary metabolism during hyperoxia in human retinal endothelial cells (RECs) and human retinal Müller glia, which coexist through glutamine consumption and production, respectively. Using a stable isotope labeling technique in human RECs and human Müller cells in culture, here we show that Müller cells in hyperoxia block entry of glycolytic carbon into the tricarboxylic acid (TCA) cycle and instead oxidize glutamine. In hyperoxia, catabolism of glutamine increased ammonium release by 2-fold. Hyperoxia induces glutamine-fueled anaplerosis that reverses basal Müller cell metabolism from production to consumption of glutamine.
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