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Mus musculus
12 Downloadable Samples
Description
Primordial germ cell (PGC) development is characterized by global epigenetic remodeling, which resets genomic potential and establishes an epigenetic ground state. Here we recapitulate PGC specification in vitro from naive embryonic stem cells and characterize the early events of epigenetic reprogramming during the formation of the human and mouse germline. Following rapid de novo DNA methylation during priming to epiblast-like cells, methylation is globally erased in PGC-like cells (PGCLCs). Repressive chromatin marks (H3K9me2/3) and transposable elements are enriched at demethylation resistant regions, while active chromatin marks (H3K4me3 or H3K27ac) are more prominent at regions that demethylate faster. The dynamics of specification and epigenetic reprogramming show species-specific differences, in particular markedly slower reprogramming kinetics in the human germline. Differences in developmental kinetics between species may be explained by differential regulation of epigenetic modifiers. Our work establishes a robust and faithful experimental system of the early events of epigenetic reprogramming and its regulation in the germline. Overall design: mRNA-seq, BS-seq and PBAT of different time-points during human and mouse in vitro PGC-like cell specification
Publication Title
Comparative Principles of DNA Methylation Reprogramming during Human and Mouse In Vitro Primordial Germ Cell Specification.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 31 Downloadable Samples
- Illumina HiSeq 2500
Description
DNA methylation and other repressive epigenetic marks are erased genome-wide in mammalian primordial germ cells (PGCs), the early embryo and in naïve embryonic stem cells (ESCs). This is a critical phase for transposon element (TE) defense since presumably alternative pathways need to be employed to limit their activity. It has been reported that pervasive transcription is enriched for TEs in ESCs in comparison to somatic cells. Here we test the hypothesis that pervasive transcription overlapping TEs forms a sensor for loss of their transcriptional repression. Overlapping sense and antisense transcription is found in TEs, and the increase of sense transcription induced by acute deletion of DNMT1 leads to the emergence of small RNAs. These small RNAs are loaded into ARGONAUTE 2 suggesting an endosiRNA mechanism for transposon silencing. Indeed, deletion of DICER reveals this mechanism to be important for silencing of certain transposon classes, while others are additionally repressed by deposition of repressive histone marks. Our observations suggest that pervasive transcription overlapping with TEs resulting in endosiRNAs is a transposon sensor that restrains their activity during epigenetic reprogramming in the germline. Overall design: Total RNA-seq libraires (2 biological replicates of 16 samples, 1 biological replicate of 1 sample)
Publication Title
An endosiRNA-Based Repression Mechanism Counteracts Transposon Activation during Global DNA Demethylation in Embryonic Stem Cells.
Sample Metadata Fields
Specimen part, Subject
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GSE42637- Homo sapiens
- 6 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Recently global gene expression profiling of patients samples lead to a molecular definition of Burkitt Lymphoma (BL) with lymphocyte enhancer-binding factor 1 (LEF1) as a signature gene. Here we report the discovery of nucleic LEF1 in a very high proportion of BL cases (15/18) and LEF1 target genes. Germinal center B cells were devoid of detectable nuclear LEF1 expression as mantle cell lymphoma (0/5), marginal zone lymphoma (0/6), follicular lymphoma (0/12) or diffuse large B cell lymphoma (DLBCL) (1/31). Using whole genome gene expression profiling after transient knockdown of LEF1 in BL cell lines, new LEF1 target genes were identified. The joint expression of these genes in primary BL samples shows that LEF1 is not only expressed aberrantly in BL but also transcriptionally active. Our study identified aberrantly expressed LEF1 and its target genes suggesting an important functional role in BLs.
Publication Title
Aberrant lymphocyte enhancer-binding factor 1 expression is characteristic for sporadic Burkitt's lymphoma.
Sample Metadata Fields
Cell line
View Samples- Mus musculus
- 8 Downloadable Samples
- Illumina HiSeq 2000
Description
DNA methylation is the net result of deposition by DNA methyltransferases (DNMT1, 3A and 3B) and removal by the Ten-Eleven Translocation 1-3 (TET1-3) family of proteins and/or passive loss by replication. The relative contribution of the individual enzymes and pathways is only partially understood. Here we comprehensively analyzed and mathematically simulated the dynamics of DNA de-methylation during the reprogramming of the hypermethylated serum-cultured mouse embryonic stem cells (ESCs) to the hypomethylated 2i-cultured ground state of mESC. We show that DNA demethylation readily occurs in TET[1-/-, 2-/-] ESCs with similar kinetics as their WT littermates. Vitamin C activation of TET causes accelerated and more profound DNA demethylation without markedly affecting reprogramming kinetics. We developed a mathematical model that highly accurately predicts the global level of 5methyl- and 5hydroxymethylcytosine during the transition. Modeling and experimental validation show that the concentration of DNMT3A and DNMT3B determines the steady state level of global DNA methylation and absence of DNMT3A/B even in continued presence of DNMT1 results in gradual loss of 5mC. Taken together, DNMT1 alone is insufficient to maintain DNA methylation but requires the action of DNMT3A/3B that act as a “dimmer switches”. Overall design: RNA-seq time series was performed during the early time phase of serum to 2i transition in the presence and absence of vitamin C (4h, 16h,24h, 32h), 1 replicate
Publication Title
Impairment of DNA Methylation Maintenance Is the Main Cause of Global Demethylation in Naive Embryonic Stem Cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 22 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Expression data of BL2 Burkitt Lymphoma cell line (controls and samples treated with different B cell specific stimuli)
Publication Title
Global gene expression changes of in vitro stimulated human transformed germinal centre B cells as surrogate for oncogenic pathway activation in individual aggressive B cell lymphomas.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 127 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2), Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Identification of a new gene regulatory circuit involving B cell receptor activated signaling using a combined analysis of experimental, clinical and global gene expression data.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Time
View Samples- Homo sapiens
- 33 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
To discover new essential regulatory pathways in B lymphoma cells a combined analysis of experimental and clinical high throughput data was performed. Among others, a specific cluster of coherently expressed genes named BCR.1 was identified in primary lymphoma samples. These coherently expressed genes are suppressed by -IgM treatment of lymphoma cells in vitro. This B cell receptor activation leads to a G2 phase prolongation, delayed entry into the M phase, an overall diminished capacity of the cells to enter into mitosis and defects in metaphases. Cytogenetic changes are detected under long term -IgM treatment. Furthermore, an inverse correlation of BCR.1 genes with c-Myc coregulated genes in distinct groups of lymphoma patients is observed. In addition to the impact of c-Myc in the regulation of cell cycle regulators, BCR.1 genes are regulated by a combined action of IKK2, MAPK14 and JNK. Finally, the BCR.1 index discriminates activated B cell like and germinal centre B cell like diffuse large B cell lymphoma. Therefore, a new regulatory circuit is described affecting cell cycle and chromosome instability in B cells.
Publication Title
Identification of a new gene regulatory circuit involving B cell receptor activated signaling using a combined analysis of experimental, clinical and global gene expression data.
Sample Metadata Fields
Specimen part, Time
View Samples- Homo sapiens
- 20 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
To discover new essential regulatory pathways in B lymphoma cells a combined analysis of experimental and clinical high throughput data was performed. Among others, a specific cluster of coherently expressed genes named BCR.1 was identified in primary lymphoma samples. These coherently expressed genes are suppressed by -IgM treatement of lymphoma cells in vitro. This B cell receptor activation leads to a G2 phase prolongation, delayed entry into the M phase, an overall diminished capacity of the cells to enter into mitosis and defects in metaphases. Cytogenetic changes are detected under long term -IgM treatment. Furthermore, an inverse correlation of BCR.1 genes with c-Myc coregulated genes in distinct groups of lymphoma patients is observed. In addition to the impact of c-Myc in the regulation of cell cycle regulators, BCR.1 genes are regulated by a combined action of IKK2, MAPK14 and JNK. Finally, the BCR.1 index discriminates activated B cell like and germinal centre B cell like diffuse large B cell lymphoma. Therefore, a new regulatory circuit is described affecting cell cycle and chromosome instability in B cells.
Publication Title
Identification of a new gene regulatory circuit involving B cell receptor activated signaling using a combined analysis of experimental, clinical and global gene expression data.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Cyclin C was cloned as a growth-promoting G1 cyclin, and was also shown to regulate gene transcription. Here we report that in vivo cyclin C acts as a haploinsufficient tumour suppressor, by controlling Notch1 oncogene levels. Cyclin C activates an 'orphan' CDK19 kinase, as well as CDK8 and CDK3. These cyclin-C-CDK complexes phosphorylate the Notch1 intracellular domain (ICN1) and promote ICN1 degradation. Genetic ablation of cyclin C blocks ICN1 phosphorylation in vivo, thereby elevating ICN1 levels in cyclin-C-knockout mice. Cyclin C ablation or heterozygosity collaborates with other oncogenic lesions and accelerates development of T-cell acute lymphoblastic leukaemia (T-ALL). Furthermore, the cyclin C encoding gene CCNC is heterozygously deleted in a significant fraction of human T-ALLs, and these tumours express reduced cyclin C levels. We also describe point mutations in human T-ALL that render cyclin-C-CDK unable to phosphorylate ICN1. Hence, tumour cells may develop different strategies to evade inhibition by cyclin C.
Publication Title
Cyclin C is a haploinsufficient tumour suppressor.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 21 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Pediatric high-grade gliomas (pHGGs) harboring the K27M mutation of H3F3A (histone H3.3) are characterized by global reduction of the repressive histone mark H3K27me3 and DNA hypomethylation.
Publication Title
Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas.
Sample Metadata Fields
Sex, Age, Disease, Disease stage
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