Transcriptomic analysis of THAP1 mediated oligodendrocyte development
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE161556 | GEO | 2021/04/24
REPOSITORIES: GEO
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Project description:Loss of function mutations in the transcription factor THAP1 cause DYT6 dystonia, a childhood-onset motor disorder. DYT6 subjects display abnormalities in the white matter regions of the brain. Here, we generated conditional THAP1 knockout mice and analyzed the gene expression profiles from motor regions of mice brains to identify a role for THAP1 in the control of myelination
2017-07-10 | GSE97372 | GEO
Project description:Transcriptomic analysis of THAP1 mediated oligodendrocyte development
| PRJNA678707 | ENA
Project description:The mature CNS contains PDGFRA+ ‘oligodendrocyte progenitor cells’ (OPC) which may remain quiescent, proliferate, or differentiate into oligodendrocytes. In human gliomas, rapidly proliferating Olig2+ cells resembling OPCs are frequently observed. We sought to identify, in vivo, candidate pathways uniquely required for OPC differentiation or quiescence. Using the bacTRAP methodology, we generated and analyzed mouse lines for translational profiling the major cells types (including OPCs), in the normal mouse brain. We then profiled oligodendoglial (Olig2+) cells from a mouse model of Pdgf-driven glioma. This analysis confirmed that Olig2+ tumor cells are most similar to OPCs, yet, it identified differences in key progenitor genes - candidates for promotion of differentiation or quiescence. There are two datasets here. One characterizes the normal translational profiles of neurons, astrocytes, mature and immature oligodendrocytes. Each cell type was profiled in triplicate, from pools of at least two mice, and total RNA controls were collected in parallel. The second dataset includes translational profiles of Olig2 positive cells from tumors form several variations of a murine model of glioma. Each variation was collected at least in triplicate, and total RNA controls were analyzed in parallel. All translational profiles were generated using the Translating Ribosome Affinity Purification protocol.
2012-10-04 | E-GEOD-30626 | biostudies-arrayexpress
Project description:The zinc finger protein ZFP24 is critical for CNS myelination. Nonetheless, the mechanism by which ZFP24 controls myelination is unknown. Here we use chromatin IP (ChIP) to map ZFP24 binding sites in oligodendrocyte progenitor cells (OPC) and differentiated oligodendrocytes (OLG). We find that ZFP24 directly binds the enhancer regions of genes important for oligodendrocyte differentiation and myelination and mediates their expression. We demonstrate that ZFP24 undergoes phosphorylation and dephosphorylation in oligodendrocyte lineage cells and that ZFP24 binding to DNA is controlled by its phosphorylated state such that only the non-phosphorylated form of the protein, predominantly found in mature oligodendrocytes, mediates expression of myelin protein genes. We have also identified key ZFP24 downstream target genes. Among these, we show that enforced expression of the crucial myelin transcription factor MYRF can rescue myelin proteins gene expression in ZFP24 -ablated cells. Our data also suggest that ZFP24 display overlapping genomic binding sites with the transcription factors MYRF, SOX10, and OLIG2 which are known to control terminal differentiation of oligodendrocytes. Though the human genome contains roughly 700 C2H2-containing zinc finger proteins, the DNA-binding sequences and the biological functions of the vast majority of them are unknown. Our findings provide a direct molecular mechanism by which dephosphorylation of ZFP24 mediates its binding to enhancer regions of genes important for oligodendrocyte differentiation and myelination, controls their expression, and as a result, regulates oligodendrocyte differentiation and CNS myelination.
2018-04-10 | GSE101535 | GEO
Project description:The mature CNS contains PDGFRA+ ‘oligodendrocyte progenitor cells’ (OPC) which may remain quiescent, proliferate, or differentiate into oligodendrocytes. In human gliomas, rapidly proliferating Olig2+ cells resembling OPCs are frequently observed. We sought to identify, in vivo, candidate pathways uniquely required for OPC differentiation or quiescence. Using the bacTRAP methodology, we generated and analyzed mouse lines for translational profiling the major cells types (including OPCs), in the normal mouse brain. We then profiled oligodendoglial (Olig2+) cells from a mouse model of Pdgf-driven glioma. This analysis confirmed that Olig2+ tumor cells are most similar to OPCs, yet, it identified differences in key progenitor genes - candidates for promotion of differentiation or quiescence.
2012-10-04 | GSE30626 | GEO
Project description:Oligodendrocytes derive from progenitors (OPC) through the interplay of epigenetic and transcriptional events. By integrating high-resolution methylomics, RNA-sequencing and multiple transgenic lines, this study defines the role of DNMT1 in developmental myelination. We detected hypermethylation of genes related to cell cycle and neurogenesis during differentiation of OPC, and yet, genetic ablation of Dnmt1 resulted in inefficient OPC expansion and severe hypomyelination associated with ataxia and tremors in mice. This phenotype was not caused by lineage switch or massive apoptosis, but was characterized by a profound defect of differentiation, associated with massive changes in exon-skipping and intron-retention splicing events, and by the activation of an endoplasmic reticulum stress response. Therefore, loss of Dnmt1 in OPC is not sufficient to induce a lineage switch, but acts as an important determinant of the coordination between RNA splicing and protein synthesis, necessary for myelin formation. mRNA profiles of P5 mouse Olig1+/+;Dnmt1flox/flox;Pdgfra-GFP and Olig1cre/+;Dnmt1flox/flox;Pdgfra-GFP sorted OPC were generated by RNA-sequencing, in triplicate, using Illumina HiSeq 2500.
2016-04-14 | E-GEOD-79018 | biostudies-arrayexpress
Project description:Goal of the experiment : Retroviral-mediated gene transfer of the THAP-zinc finger protein THAP1 inhibits endothelial cell proliferation through coordinated repression of critical cell cycle regulators and pRB-E2F target genes. Experimental design: To gain insight into the effects of THAP1 on endothelial cell growth regulatory pathways, we identified THAP1 target genes in primary human endothelial cells using oligonucleotide-based microarray technology. Human umbilical vein endothelial cells (HUVECs) were transduced with pMLV-MCS or pMLV-THAP1 retroviral expression vectors and, after 48h, cells were harvested for isolation of total RNA and preparation of Cy3- or Cy5-labeled cRNA probes, which were hybridized to DNA microarrays that contained 22 000 unique 60-nt oligonucleotide probes representing > 17 000 human genes. Independent microarray experiments were performed after one (#1xTHAP1) or two (#2xTHAP1) consecutive transductions using independent HUVEC primary cell cultures. Dye swap experiments were performed to eliminate the effect of dye bias, and for each gene probe, the data were subjected to statistical analysis to identify those probes for which a significant difference (p value < 0.01) in mean hybridization intensity was observed between HUVECs transduced with pMLV-MCS or pMLV-THAP1 retroviral expression vectors. Among the gene probes demonstrating a significant difference between the two conditions, we selected those whose expression varied in a similar manner in the two independent microarray experiments. . #2xTHAP1 experiment (Microarrays Code Bars 16011521022012 and 16011521022013): comparison of HUVEC-THAP1 and HUVEC-MCS after two consecutive retroviral transductions of HUVECs with pMLV-THAP1 or pMLV-MCS vectors (higher percentage of genes differentially expressed with p value < 0.01; higher folds) #1xTHAP1 experiment (Microarrays Code Bars 16011521025800 and 16011524025685): comparison of HUVEC-THAP1 and HUVEC-MCS after a single retroviral transduction of HUVECs with pMLV-THAP1 or pMLV-MCS vectors (lower percentage of genes differentially expressed with p value < 0.01; lower folds).
2006-09-11 | E-TABM-24 | biostudies-arrayexpress
Project description:Mutations in Brg1 can cause Coffin-Siris syndrome, where a patient had white matter defects and partial agenesis of the corpus callosum; however, Brg1 functions in CNS myelination and remyelination is unsure. We show that PDGFRa expressed prior than NG2, depletion of Brg1 at PDGFRα+ OPC leads to OPC differentiation restriction and myelin defects, also, Brg1 is critical for oligodendrocyte remyelination. Genomic occupancy and transcriptome analyses indicate that Brg1 promotes H3K27me3 and neuronal genes. Thus our findings reveal that Brg1 is a critical epigenetic programmer of CNS myelination and repair through recruiting H3K27me3 and neuronal genes, suggesting potential strategies of therapeutic intervention for Brg1-associated white matter defects.
2024-03-25 | GSE205236 | GEO
Project description:Characterizing the developmental trajectory of oligodendrocyte progenitor cells (OPC) is of great interest given the importance of these cells in the remyelination process. However, studiescof human OPC development remain limited by the availability of whole cell samples and material that encompasses a wide age range, including time of peak myelination. In this study, we apply single cell RNA sequencing to viable whole cells across the age span and link transcriptomic signatures of oligodendrocyte-lineage cells with stage-specific functional properties. Cells were isolated from surgical tissue samples of second-trimester fetal, 2 year old pediatric, 13 year old adolescent, and adult donors by mechanical and enzymatic digestion, followed by percoll gradient centrifugation. Gene expression was analyzed using droplet-based RNA sequencing (10X Chromium). Louvain clustering analysis identified 3 distinct cellular subpopulations based on 5613 genes, comprised of an early OL precursor cell (e-OPC) group, a late OPC group (l-OPC), and a mature OL (MOL) group. Gene ontology terms enriched for e-OPCs were cell cycle and development, for l-OPCs were extracellular matrix and cell adhesion, and for MOLs were myelination and cytoskeleton. The e-OPCs were mostly confined to the premyelinating fetal group, and the l-OPCs were most highly represented in the pediatric age group, corresponding to the peak age of myelination. Cells expressing a signature characteristic of l-OPCs were identified in the adult brain in situ using RNAScope. These findings highlight the transcriptomic variability in OL-lineage cells before, during, and after peak myelination and contribute to identifying novel pathways required to achieve remyelination.
2021-01-12 | GSE155488 | GEO
Project description:We performed an integrated study of genome-wide OLIG2 binding and the epigenetic modification status of both coding and non-coding genes during three stages of oligodendrocyte differentiation in vivo: Neural Stem Cells (NSC), Oligodendrocyte Progenitor Cells (OPC), and Newly Formed Oligodendrocytes (NFO). We found that 613 lncRNAs have OLIG2-binding sites and are expressed in at least one cell type, which can potentially be activated or repressed by OLIG2. 48 of them have increased expression in oligodendrocyte lineage cells. Predicting lncRNA functions by using a “guilt-by-association” approach revealed that the functions of these 48 lncRNAs were enriched in ‘oligodendrocyte development and differentiation’. Additionally, bivalent genes are known to play essential roles during embryonic stem cell differentiation. We identified bivalent genes in NSC, OPC, and NFO, and found that some bivalent genes bound by OLIG2 are dynamically regulated during oligodendrocyte development. Importantly, we have identified AU-rich elements (AREs) in the 3’-UTRs of Olig2 mRNAs. We unveiled a previously unknown mechanism that, in addition to transcriptional regulation via DNA binding, OLIG2 could post-transcriptionally self-regulate expression through interaction with the 3’-UTR of its own mRNA.
2021-07-08 | GSE155890 | GEO