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Clonal Immortalized Human Glial Cell Lines Support Varying Levels of JC Virus Infection due to Differences in Cellular Gene Expression

ABSTRACT: JC virus (JCV) is a ubiquitous human polyomavirus that causes the demyelinating disease Progressive Multifocal Leukoencephalopathy (PML). JCV replicates in limited cell types in culture, predominantly in human glial cells. Thus, productive JCV infection is an indicator of the host cell transcription environment. Following introduction of a replication defective SV40 mutant that expressed large T protein into a heterogeneous culture of human fetal brain cells, multiple phenotypes became immortalized (SVG cells). A subset of SVG cells could support JCV replication. This mixed culture was called SVG cells. In the current study, clonal cell lines were selected from the original SVG cell culture. The SVG-5F4 clone showed low levels of viral growth. The SVG-10B1 clone was highly permissive for JCV DNA replication and gene expression. Microarray analysis revealed that viral infection did not significantly change gene expression in these cells. More resistant 5F4 cells expressed high levels of transcription factors known to inhibit JCV transcription. Interestingly, 5F4 cells highly expressed RNA of markers of Bergman or radial glia and 10B1 cells had high expression of markers of immature glial cells and activation of transcription regulators important for stem/progenitor cell self-renewal. These SVG-derived clonal cell lines provide a biologically relevant model to investigate cell type differences in JCV host range and pathogenesis, as well as neural development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE45639 | GEO | 2013/10/17

SECONDARY ACCESSION(S): PRJNA195455

REPOSITORIES: GEO

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Clonal Immortalized Human Glial Cell Lines Support Varying Levels of JC Virus Infection due to Differences in Cellular Gene Expression

Project description:JC virus (JCV) is a ubiquitous human polyomavirus that causes the demyelinating disease Progressive Multifocal Leukoencephalopathy (PML). JCV replicates in limited cell types in culture, predominantly in human glial cells. Thus, productive JCV infection is an indicator of the host cell transcription environment. Following introduction of a replication defective SV40 mutant that expressed large T protein into a heterogeneous culture of human fetal brain cells, multiple phenotypes became immortalized (SVG cells). A subset of SVG cells could support JCV replication. This mixed culture was called SVG cells. In the current study, clonal cell lines were selected from the original SVG cell culture. The SVG-5F4 clone showed low levels of viral growth. The SVG-10B1 clone was highly permissive for JCV DNA replication and gene expression. Microarray analysis revealed that viral infection did not significantly change gene expression in these cells. More resistant 5F4 cells expressed high levels of transcription factors known to inhibit JCV transcription. Interestingly, 5F4 cells highly expressed RNA of markers of Bergman or radial glia and 10B1 cells had high expression of markers of immature glial cells and activation of transcription regulators important for stem/progenitor cell self-renewal. These SVG-derived clonal cell lines provide a biologically relevant model to investigate cell type differences in JCV host range and pathogenesis, as well as neural development. 13 Human samples: 3 SVG 10B1 clones 14 days post mock-infection, 3 SVG 10B1 clones 14 days post JCV Mad-4 strain infection, 3 SVG 5F4 clones 14 days post mock-infection, 4 SVG 5F4 clones 14 days post JCV Mad-4 strain infection.

2013-10-17 | E-GEOD-45639 | biostudies-arrayexpress

Comparison of gene expression in SVG-A glial cells and SVGR2 glial cells

2007-05-25 | GSE7819 | GEO

Transcription profiling of human SVG-A glial cells and SVGR2 glial cells

Project description:SVGR2 cells are glial cells which are derived from SVG-A cells. They were created by subjecting SVG-A cells to multiple rounds of lytic infection by the human polyomavirus JCV. SVGR2 cells are the cells that survived this process and are resistant to JCV infection. This experiment was designed to identify gene expression differences that may be responsible for SVGR2 resistance to JCV. Experiment Overall Design: SVG-A and SVGR2 cells are transformed cell lines. To eliminate gene expression differences that may have occurred due to genetic instability of these cell lines three subclones of each of the cell lines were created and used as a triplicate in the comparison. Total RNA was extracted from cells that had been left at 100% confluency for one day using the Qiagen RNeasy kit. cDNA was hybridized to the Affymetrix Human GeneChips U133A or U133B according to Affymetrix gudielines.

2008-11-07 | E-GEOD-7819 | biostudies-arrayexpress

Homo sapiens

Project description:Comparison of gene expression in SVG-A glial cells and SVGR2 glial cells

| PRJNA100049 | ENA

Cell of origin epigenetic priming determines susceptibility to Tet2 mutation

Project description:Hematopoietic stem cell (HSC) mutations can result in clonal hematopoiesis (CH) with heterogeneous clinical outcomes. Here, we investigated how the cell state preceding Tet2 mutation impacts the pre-malignant phenotype. Using an inducible system for clonal analysis of myeloid progenitors, we found that the epigenetic features of clones at similar differentiation status were highly heterogeneous and functionally responded differently to Tet2 mutation. Cell differentiation stage also influenced Tet2 mutation response indicating that the cell of origin's epigenome modulates clone-specific behaviors in CH. Molecular features associated with higher risk outcomes include Sox4 that sensitized cells to Tet2 inactivation, inducing dedifferentiation, altered metabolism and increasing the in vivo clonal output of mutant cells, as confirmed in primary GMP and HSC models. Our findings validate the hypothesis that epigenetic features can predispose specific clones for dominance, explaining why identical genetic mutations can result in different phenotypes.

1970-01-01 | MTBLS9914 | MetaboLights

Transcriptional response to Notch activation in SVG-A cells

Project description:SVG-A cells are immortalized fetal astrocytes that respond to Notch signaling. We characterized the transcriptional response to Notch activation in this cell line by performing RNA-seq on cells grown on tissue culture dishes coated with JAGGED1, a Notch ligand. Differential gene expression analysis shows induction of both canonical Notch responsive genes, as well as cell-type specific Notch responsive genes.

2024-02-28 | GSE235637 | GEO

Genome-wide analysis of gene expression during somatic cell reprogramming

Project description:Reprogrammed mouse embryonic fibroblasts generated clonal cell lines were analysed during maintained expression of the four reprogramming transcription factors (C-Myc, Oct4, Sox2, Klf4). The transgene expressing clonal cell lines segregated in to two Nanog positive cell types, F-class and C-class, that both differentiate in to three germ layers. The emergence of F-class cells is dependent on the expression of all four factors with a necessity for high levels of transgene expression. The F-class cells represent a novel and stable cell state. Mouse embryonic fibroblasts were reprogrammed using four transcription factors (C-Myc, Oct4, Sox2, Klf4) and clonal cell lines established. Cell lines were maintained in doxycycline supplemented media to sustain transgene expression. Global gene expression profile analysis was performed on the clonal cell lines at day16, with respect to embryonic stem cells and parental fibroblast cells. F-class cells (clone 1) were maintained for a further two weeks and found not to acquire expression of ESC associated genes.

2014-12-10 | E-GEOD-49940 | biostudies-arrayexpress

Clonal multi-omics reveals Bcor as a regulator of dendritic cell development and its action at a clonal level

Project description:Despite major developments in single cell multi-omics approaches, a single stem or progenitor cell can only be tested once. Here we develop ‘clonal multi-omics’, where recent daughters of a clone act as surrogates of the parental cell allowing multiple tests of its molecular profile and/or cellular fate under different conditions. We first present SIS-seq – a novel clonal method whereby siblings are examined in parallel for gene expression by RNA-seq, or for fate after culture. We use this method to identify, then validate using CRISPR, the genes expressed in single haematopoietic progenitors that control the development of the different dendritic cell (DC) subtypes. In this way, Bcor is identified as a suppressor of plasmacytoid DC (pDC) and conventional DC subtype 2 (cDC2) numbers during Flt3 ligand-mediated ‘emergency’ DC development. Using a complementary method SIS-skew – where WT and BcorKO siblings of the same clone are examined in parallel for fate – we discover that Bcor restricts clonal expansion, especially for generation of cDC2s, and suppresses clonal fate potential, especially for pDCs. SIS-seq and SIS-skew therefore represent novel and broadly applicable clonal multi-omics approaches that could reveal the molecular and cellular mechanisms governing stem, immune, reprogrammed and cancer cell function at a single cell level, including after genetic or extrinsic factor perturbation.

2020-07-01 | GSE153675 | GEO

Clonal multi-omics in DC development

Project description:Despite major developments in single cell multi-omics approaches, a single stem or progenitor cell can only be tested once. Here we develop ‘clonal multi-omics’, where recent daughters of a clone act as surrogates of the parental cell allowing multiple tests of its molecular profile and/or cellular fate under different conditions. We first present SIS-seq – a novel clonal method whereby siblings are examined in parallel for gene expression by RNA-seq, or for fate after culture. We use this method to identify, then validate using CRISPR, the genes expressed in single haematopoietic progenitors that control the development of the different dendritic cell (DC) subtypes. In this way, Bcor is identified as a suppressor of plasmacytoid DC (pDC) and conventional DC subtype 2 (cDC2) numbers during Flt3 ligand-mediated ‘emergency’ DC development. Using a complementary method SIS-skew – where WT and BcorKO siblings of the same clone are examined in parallel for fate – we discover that Bcor restricts clonal expansion, especially for generation of cDC2s, and suppresses clonal fate potential, especially for pDCs. SIS-seq and SIS-skew therefore represent novel and broadly applicable clonal multiomics approaches that can reveal the molecular and cellular mechanisms governing cell function at a single cell level, including after genetic or extrinsic factor perturbation. This SuperSeries is composed of the SubSeries listed below.

2020-07-01 | GSE153676 | GEO

Somatic Mutations and Cell Lineage in the Human Brain

Project description:Genetic mutations causing human disease are conventionally thought to be inherited from one's parents and present in all somatic (body) cells. Increasingly however, somatic mutations are implicated in neurological diseases. Somatic mutations that arise during the cell divisions of prenatal brain development are inherited in clonal fashion and can cause neurodevelopmental diseases, even when present at low levels of mosaicism. In this study we use whole genome sequencing of single neurons and bulk tissue to identify somatic mutations in control, and some disease, brains to: 1) identify and catalogue the mutations which shape the somatic neuronal genome; 2) perform a cell lineage analysis of the adult human brain using clonal somatic mutations in cortical neurons; 3) determine patterns of somatic mutations at different ages and in aging related disease phenotypes; and 4) relate cell lineage patterns to cell phenotype in the human brain by separating neuronal, glial, and other cell types.

| phs001485 | dbGaP

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