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GSE86147
Homo sapiens
10 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Previous study demonstrated that HDAC3 has a critical role in MM proliferation; however, the underlying mechanism has not yet been elucidated. We identify that HDAC3 inhibition targets DNMT1 through dual regulations. We demonstrate that knockdown of DNMT1 leads to apoptosis and significant growth inhibition in myeloma cells. HDAC3 inhibition by gene silencing or HDAC3 selective inhibitor BG45 downregulates an oncoprotein c-Myc through its acetylation. c-Myc directly regulates DNMT1 expression at its enhancer region. Furthermore, HDAC3 directly regulates the stability of DNMT1 protein through its acetylation. Pharmaceutical inhibition of HDAC3 and DNMT1 synergistically induce MM growth inhibition in in vitro and in vivo settings.
Publication Title
HDAC3 regulates DNMT1 expression in multiple myeloma: therapeutic implications.
Sample Metadata Fields
Cell line
View Samples- Macaca mulatta
- 22 Downloadable Samples
- Affymetrix Rhesus Macaque Genome Array (rhesus)
Description
Metabolic, mitochondrial and behavioral correlations with transcriptional profiles from the CA1 and DG hippocampal regions of young and aged rhesus macaque. Increasing evidence indicates that obesity correlates with impaired cognitive performance during normal aging and is a major risk factor for Alzheimers disease. However, little is known regarding how peripheral metabolic variables affect cellular pathways in brain regions important for memory. Brain inflammation, mitochondrial dysregulation, and altered transcriptional regulation have all been found to occur with aging, and recent microarray analyses in rodent models have linked these processes and others to age-related memory impairment. However, whether these brain changes are also associated with metabolic variables is not known. Aging monkeys exhibit several metabolic changes similar to those seen in humans. Here, we tested peripheral-brain relationships in six young (7.0 +/- 0.3 years) and six aged (23.5 +/- 0.7 years) female rhesus monkeys. Animal cognition was gauged with a variable delay task; blood constituents were assessed with a serum chemistry panel emphasizing markers of metabolic dysfunction; mitochondrial function was measured from the hippocampus of one hemisphere; and the CA1 and dentate gyrus regions of the other hippocampus were dissected out for gene expression microarray analysis. Aged animals showed reduced performance on the behavioral task, exhibited aspects of metabolic dysregulation including increased insulin, triglyceride, and chylomicron levels (consolidated into a peripheral metabolic index), and showed a significant age-related reduction in State III oxidation, a measure of mitochondrial function. Microarray analyses revealed hundreds of genes that correlated with the peripheral metabolic index. However, DAVID statistical pathway analyses showed that upregulated inflammatory genes in CA1 and downregulated transcriptional regulation genes in dentate gyrus and CA1 were particularly overrepresented among genes correlated with the peripheral index. Thus, the association of metabolic variables with specific neuropathological processes in different regions of the hippocampal formation may have implications for mechanisms through which peripheral metabolism alters the risk for Alzheimers disease.
Publication Title
Aging-related gene expression in hippocampus proper compared with dentate gyrus is selectively associated with metabolic syndrome variables in rhesus monkeys.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 8 Downloadable Samples
NextSeq 500
Description
KRAS mutation is present in about 30% of human lung adenocarcinomas. While recent advances in targeted therapy have shown great promise, KRAS remains undruggable and concurrent alterations in tumor suppressors render KRAS mutant tumors even more resistant to existing therapies. Contributing to the refractoriness of KRAS mutant tumors harboring these co-mutations are immunosuppressive mechanisms such as increased presence of suppressive Tregs in tumors and elevated expression of the inhibitory receptor PD-1 on tumor-infiltrating T cells. BET bromodomain inhibitors demonstrate clinical benefit in hematologic malignancies, and prior reports demonstrate their Treg-disruptive effects in a NSCLC model. Targeting PD-1 inhibitory signals through anti-PD-1 antibody blockade has also shown substantial therapeutic impact in lung cancer although these outcomes are still limited to a minor pool of patients. We therefore hypothesized that the BET bromodomain inhibitor JQ1 would synergize with PD-1 blockade to promote robust anti-tumor response in lung cancer. In the present study, using Kras+/LSL-G12D; Trp53L/L (KP) mouse models of non-small cell lung cancer, we identified cooperative effects between JQ1 and anti-PD-1 antibody that included reduced numbers of tumor-infiltrating Tregs and enhanced activation of tumor-infiltrating T cells, which exhibited a Th1 cytokine profile that favored their demonstrated improved effector function. Furthermore, lung-tumor-bearing mice under this combinatorial treatment regimen showed robust and long-lasting anti-tumor responses compared to either agent alone, culminating in substantial improvement in the survival of treated mice. Thus, combining BET bromodomain inhibition with immune checkpoint blockade offers a promising therapeutic approach for solid malignancies such as lung adenocarcinoma. Overall design: Gene expression analyses of tumor nodules in lung tumor-bearing mice treated with Vehicle (control), JQ1 (Bromodomain inhibitor) and/or anti-PD-1 antibody
Publication Title
BET Bromodomain Inhibition Cooperates with PD-1 Blockade to Facilitate Antitumor Response in <i>Kras</i>-Mutant Non-Small Cell Lung Cancer.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Homo sapiens
- 40 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Activated B-cell-like (ABC) and germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL) represent the two major molecular DLBCL subtypes. They are characterized by differences in clinical course and by divergent addiction to oncogenic pathways. To determine activity of novel compounds in these two subtypes, we conducted an unbiased pharmacologic in vitro screen. The phosphatidylinositol-3-kinase (PI3K) alpha/delta (PI3Ka/d) inhibitor AZD8835 showed marked potency in ABC DLBCL models, whereas the protein kinase B (AKT) inhibitor AZD5363 induced apoptosis in PTEN-deficient DLBCLs. These in vitro results were confirmed in various cell line xenograft and patient-derived xenograft mouse models in vivo. Treatment with AZD8835 induced inhibition of nuclear factor kappa-B (NF-kB) signaling, prompting us to combine AZD8835 with the Brutons tyrosine kinase (BTK) inhibitor ibrutinib. This combination was highly synergistic and effective both in vitro and in vivo. In contrast, the AKT inhibitor AZD5363 was effective in PTEN-deficient DLBCLs through downregulation of the oncogenic transcription factor MYC. Collectively our data suggest that patients should be stratified according to their oncogenic dependencies when treated with PI3K and AKT inhibitors.
Publication Title
Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of DLBCL.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 3 Downloadable Samples
- Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
The protease activity of the paracaspase MALT1 plays an important role in antigen receptor-mediated lymphocyte activation by controlling the activity of the transcription factor NF-kB and is thus essential for the expression of inflammatory target genes.
Publication Title
MALT1 Protease Activity Controls the Expression of Inflammatory Genes in Keratinocytes upon Zymosan Stimulation.
Sample Metadata Fields
Treatment
View Samples- Mus musculus
- 47 Downloadable Samples
- IlluminaHiSeq2500
Description
RNA-seq was performed to compare expression pattern of musles taken form two mice strains- mdx and mdx/Runx1f/f, which are double KO carrting a muscle specific ablation of Runx1 using a Myf5-Cre. This comparison revealed the Runx1- responsive gene set in mdx muscles. we could cross this data with prior retrived datd from privous experiments found in this GEO quary, to pinpiont Runx1 target genes in muscle rgeneration Overall design: RNA was extracted form soleus muscles of 2 months old mice, n=3,4 for mdx and mdx/Runx1f/f, respectively . Differentially expressed genes were discovered using the DeSeq2 software
Publication Title
Genomic-wide transcriptional profiling in primary myoblasts reveals Runx1-regulated genes in muscle regeneration.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Genomic-wide transcriptional profiling in primary myoblasts reveals Runx1-regulated genes in muscle regeneration.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Dissecting the retinoid-induced differentiation of F9 embryonal stem cells by integrative genomics.
Sample Metadata Fields
Cell line, Time
View Samples- Homo sapiens
- 17 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Altering TET dioxygenase levels within physiological range affects DNA methylation dynamics of HEK293 cells.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Homo sapiens
- 5 Downloadable Samples
Affymetrix Mapping 250K Nsp SNP Array (mapping250knsp), Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Reconstruction of gene regulatory networks reveals chromatin remodelers and key transcription factors in tumorigenesis.
Sample Metadata Fields
Specimen part, Cell line
View Samples