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SRP055990
Rattus norvegicus
5 Downloadable Samples
Description
The heart adapts to increased workload through hypertrophic growth of cardiomyocytes. Although beneficial when induced physiologically by exercise, pathological cues including hypertension cause reexpression of fetal genes and dysfunctional hypertrophy, with lasting consequences for cardiac health. We hypothesised that these differences are driven by changes in chromatin-encoded cellular memory. We generated genome-wide maps of transcription and of two stable epigenetic marks, H3K9me2 and H3K27me3, specifically in hypertrophied cardiomyocytes, by selectively flow-sorting their nuclei. This demonstrated a pervasive loss of euchromatic H3K9me2 specifically upon pathological but not physiological hypertrophy, derepressing genes associated with pathological hypertrophy. Levels of the H3K9 methyltransferases, G9a and GLP, were correspondingly reduced. Importantly, pharmacological or genetic inactivation of these enzymes was sufficient to induce pathological hypertrophy and the dedifferentiation associated with it. These findings suggest novel therapeutic opportunities by defining an epigenetic state of cardiomyocytes, acquired during maturation, which is required for maintaining cardiac health. Overall design: Examination of 2 different histone modifications and RNA expression in cardiomyocyte nuclei flow-sorted from hypertrophic rat hearts
Publication Title
The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophy.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 22 Downloadable Samples
- IlluminaHiSeq2000
Description
The translational control of oncoprotein expression is implicated in many cancers. Here we report an eIF4A/DDX2 RNA helicase-dependent mechanism of translational control that contributes to oncogenesis and underlies the anticancer effects of Silvestrol and related compounds. For example, eIF4A promotes T-ALL development in vivo and is required for leukaemia maintenance. Accordingly, inhibition of eIF4A with Silvestrol has powerful therapeutic effects in vitro and in vivo. We use transcriptome-scale ribosome footprinting to identify the hallmarks of eIF4A-dependent transcripts. These include 5'UTR sequences such as the 12-mer guanine quartet (CGG)4 motif that can form RNA G-quadruplex structures. Notably, among the most eIF4A-dependent and Silvestrol-sensitive transcripts are a number of oncogenes, super-enhancer associated transcription factors, and epigenetic regulators. Hence, the 5'UTRs of selected cancer genes harbour a targetable requirement for the eIF4A RNA helicase. Overall design: Comparison of ribosome-protected RNA for drug treated and DMSO treated KOPT-K1 cell, two replicates of ribosome-protected RNA sequencing and three replicates of RNA-seq.
Publication Title
RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 8 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 8 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Here we modeled T-ALL resistance to Notch inhibition, identifying persister cells that readily expand in the presence of gamma secretase inhibitor (GSI) and the absence of Notch signaling. Rare persister cells are already present in nave T-ALL populations, and the reversibility of the phenotype is suggestive of an epigenetic mechanism. Relative to GSI-sensitive cells, persisters activate distinct signaling and gene expression programs, and exhibit global chromatin compaction. A shRNA screen identified chromatin regulators whose depletion preferentially impairs persister cell viability, including BRD4, an acetyl-histone reader. BRD4 is up-regulated in the persisters and binds enhancers near genes with critical functions in T-ALL, including MYC and BCL2. Treatment of persisters with the BRD4 inhibitor JQ1 down-regulates these targets and induces growth arrest and apoptosis, at doses well tolerated by GSI-sensitive cells. Prompted by these findings, we examined and established the efficacy of GSI JQ1 combination therapy against primary human leukemias in vivo. Our findings establish a role for epigenetic heterogeneity in leukemia drug resistance and suggest the potential of combination therapies that include epigenetic modulators to prevent and treat resistant disease.
Publication Title
An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 69 Downloadable Samples
- Illumina MouseRef-8 v2.0 expression beadchip
Description
Microarray analysis revealed that changes in genes expressions are brain region-dependent; expression of several genes are affected by point mutation L100P, which was verified by RT-PCR (Lcn2, Cyr61, Slc6a12, Slc40a1, Egr2), a few genes are affected by genotype and valproate (Dusp1 and Purb), suggesting their role in valproate-induced benificial effect on sensorimotor gaiting in Disc1-L100P mutant mice. The final conclusion will be drawn after series of RT-PCR confirmation.
Publication Title
Genetic and pharmacological evidence for schizophrenia-related Disc1 interaction with GSK-3.
Sample Metadata Fields
Sex, Specimen part, Compound
View Samples- Homo sapiens
- 36 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a), Illumina HumanHT-12 V3.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
PGC-1α, a potential therapeutic target for early intervention in Parkinson's disease.
Sample Metadata Fields
Sex, Age, Specimen part, Disease
View Samples- Homo sapiens
- 20 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Genome-wide transcriptome analysis of expression changes in Globus Pallidus interna (GPi) from Parkinson's disease brain tissue versus control brain tissue.
Publication Title
PGC-1α, a potential therapeutic target for early intervention in Parkinson's disease.
Sample Metadata Fields
Sex, Specimen part, Disease, Disease stage
View Samples- Homo sapiens
- 16 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Genome-wide transcriptome analysis of expression changes in laser-dissected SNpc neurons from Parkinson's disease brain tissue versus control brain tissue.
Publication Title
PGC-1α, a potential therapeutic target for early intervention in Parkinson's disease.
Sample Metadata Fields
Specimen part, Disease, Disease stage
View Samples- Homo sapiens
- 17 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
Systematic meta-analysis and replication of genome-wide expression studies identifies molecular pathways of Parkinson's disease.
Publication Title
PGC-1α, a potential therapeutic target for early intervention in Parkinson's disease.
Sample Metadata Fields
Age, Specimen part, Disease
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Genome-wide transcriptome analysis of expression changes in EBV transformed cell lines from the Coriell Cell Repository in Parkinson and Control subjects.
Publication Title
PGC-1α, a potential therapeutic target for early intervention in Parkinson's disease.
Sample Metadata Fields
Sex, Disease, Disease stage
View Samples