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GSE146615
Homo sapiens
144 Downloadable Samples
Illumina HumanHT-12 V4.0 expression beadchip
Description
The goal of the study was to identify genes whose aberrant expression can contribute to diabetic retinopathy. We determined differential response in gene expression to high glucose in lymphoblastoid cell lines derived from matched type 1 diabetic individuals with and without retinopathy. Those genes exhibiting the largest difference in glucose response between diabetic subjects with and without retinopathy were assessed for association to diabetic retinopathy utilizing genotype data from a meta-genome-wide association study. All genetic variants associated with gene expression (expression QTLs; eQTLs) of the glucose response genes were tested for association with diabetic retinopathy. We detected an enrichment of the glucose response gene eQTLs among small association p-values for diabetic retinopathy. Among these, we identified FLCN as a susceptibility gene for diabetic retinopathy. Expression of FLCN in response to glucose is greater in individuals with diabetic retinopathy compared to diabetic individuals without retinopathy. Three large, independent cohorts of diabetic individuals revealed an enhanced association of FLCN eQTL to diabetic retinopathy. Mendelian randomization confirmed a direct positive effect of increased FLCN expression on retinopathy in diabetic individuals. Together, our studies integrating genetic association and gene expression implicate FLCN as a disease gene in diabetic retinopathy.
Publication Title
Integration of genomics and transcriptomics predicts diabetic retinopathy susceptibility genes.
Sample Metadata Fields
Cell line
View Samples- Drosophila melanogaster
- 2 Downloadable Samples
Illumina HiSeq 2000
Description
T4 and T5 neurons are components of the neuronal circuit for motion vision in flies. To identify genes involved in neuronal computation of T4 and T5 neurons, we perfomed transcriptome analysis. Nuclei of T4 and T5 neurons were immunoprecipitated, total RNA was harvested and used for mRNA-seq with Illumina technology. In two biological replicates, we mapped 154 and 119 million reads to D. melanogaster genome. mRNA-seq provided information about expression levels of 17,468 annotated transcripts in the T4 and T5 neurons. Overall design: Cell type – specific transcriptome analysis of the RNA isolated from immunoprecipitated nuclei, performed in two biological replicates
Publication Title
RNA-Seq Transcriptome Analysis of Direction-Selective T4/T5 Neurons in Drosophila.
Sample Metadata Fields
Subject
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
The generation of induced pluripotent stem cells (iPSCs) from differentiated cells following forced expression of Oct4, Klf4, Sox2 and c-Myc (OKSM) is slow and inefficient, suggesting that transcription factors have to overcome somatic barriers that resist cell fate change. Here, we performed an ubiased serial shRNA enrichment screen to identify novel repressors of somatic cell reprogramming into iPSCs. This effort uncovered the sumoylation effector protein Sumo2 as one of the strongest roadblocks to iPSC formation. Depletion of Sumo2 both enhances and accelerates reprogramming, yielding transgene-independent, chimera-competent iPSCs after as little as 36 hours of OKSM expression. We further show that the Sumo2 pathway acts independently of exogenous c-Myc expression and in parallel with small molecule enhancers of reprogramming. Critically, suppression of SUMO2 also promotes the generation of human iPSCs. Together, our results reveal sumoylation as a crucial post-transcriptional mechanism that resists the acquisition of pluripotency from fibroblasts using defined factors.
Publication Title
A Serial shRNA Screen for Roadblocks to Reprogramming Identifies the Protein Modifier SUMO2.
Sample Metadata Fields
Sex, Specimen part, Time
View Samples- Homo sapiens
- 18 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The activation of endothelium by tumor cells is one of the main steps by tumor metastasis. The role of the blood components (platelets and leukocytes) in this process remain unclear.
Publication Title
Selectin-mediated activation of endothelial cells induces expression of CCL5 and promotes metastasis through recruitment of monocytes.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 24 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Elevated levels of androgen receptor (AR) in prostate cancer confer resistance to current antiandrogens and play a causal role in disease progression due to persistent target gene activation. Through pharmacologic and genetic approaches, we show that half of all direct AR target genes, including TMPRSS2, the primary driver of ETS fusion transcripts in 70 percent of human prostate cancers, require histone deacetylase (HDAC) activity for transcriptional activation by AR. Surprisingly, the HDAC3-NCoR complex, which typically functions to repress gene expression by nuclear receptors, is required for AR target gene activation. Prostate cancer cells treated with HDAC inhibitors have reduced AR protein levels, but we show that the mechanism of blockade of AR activity is through failure to assemble a coactivator/RNA polymerase II complex after AR binds to the enhancers of target genes. Failed complex assembly is associated with a phase shift in the cyclical wave of AR recruitment that typically occurs in response to ligand treatment. HDAC inhibitors retain the ability to block AR activity in hormone refractory prostate cancer models and therefore merit clinical investigation in this setting. HDAC-regulated AR target genes defined here can serve as biomarkers to ensure sufficient levels of HDAC inhibition.
Publication Title
Histone deacetylases are required for androgen receptor function in hormone-sensitive and castrate-resistant prostate cancer.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 19 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Elevated levels of androgen receptor (AR) in prostate cancer confer resistance to current antiandrogens and play a causal role in disease progression due to persistent target gene activation. Through pharmacologic and genetic approaches, we show that half of all direct AR target genes, including TMPRSS2, the primary driver of ETS fusion transcripts in 70 percent of human prostate cancers, require histone deacetylase (HDAC) activity for transcriptional activation by AR. Surprisingly, the HDAC3-NCoR complex, which typically functions to repress gene expression by nuclear receptors, is required for AR target gene activation. Prostate cancer cells treated with HDAC inhibitors have reduced AR protein levels, but we show that the mechanism of blockade of AR activity is through failure to assemble a coactivator/RNA polymerase II complex after AR binds to the enhancers of target genes. Failed complex assembly is associated with a phase shift in the cyclical wave of AR recruitment that typically occurs in response to ligand treatment. HDAC inhibitors retain the ability to block AR activity in hormone refractory prostate cancer models and therefore merit clinical investigation in this setting. HDAC-regulated AR target genes defined here can serve as biomarkers to ensure sufficient levels of HDAC inhibition.
Publication Title
Histone deacetylases are required for androgen receptor function in hormone-sensitive and castrate-resistant prostate cancer.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 10 Downloadable Samples
- Illumina HiSeq 2000
Description
The ubiquitous efflux transporter ATP-binding cassette sub-family C member 5 (ABCC5) is present at high levels in the blood-brain barrier, neurons and glia, but its in vivo substrates and function are not known. Untargeted metabolomic screens revealed that Abcc5-/- mice accumulate endogenous glutamate conjugates and analogs in several tissues, but brain in particular. The abundant neurotransmitter N-acetylaspartylglutamate (NAAG), for example, was over 2-fold higher in Abcc5-/- brain. In line with ABCC5-mediated transport, the metabolites that accumulated in Abcc5-/- tissues were depleted in cultured cells that overexpressed human ABCC5. Using membrane vesicles, we show that ABCC5 not only transports the metabolites detected in our screen, but also a wide range of peptides containing a C-terminal glutamate. Glutamate conjugates are of physiological relevance because they can affect the function of glutamate, the principal excitatory neurotransmitter in the brain. We found that ABCC5 also transports exogenous glutamate analogs, like the classic excitotoxic neurotoxins kainic acid, domoic acid and N-methyl-D-aspartate (NMDA) and the therapeutic glutamate analog ZJ43. Taken together, we have identified ABCC5 as a general glutamate conjugate and analog transporter that affects the disposition of endogenous metabolites, toxins and drugs. Overall design: A set of 5 wildtype brains was compared to a set of 5 Abcc5-knockout mouse brains
Publication Title
ATP-binding Cassette Subfamily C Member 5 (ABCC5) Functions as an Efflux Transporter of Glutamate Conjugates and Analogs.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
Histone deacetylases (HDACs) and acetyltransferases control the epigenetic regulation of gene expression through modification of histone marks. Histone deacetylase inhibitors (HDACi) are small molecules that interfere with histone tail modification thus altering chromatin structure and epigenetically controlled pathways. They promote apoptosis in proliferating cells and are promising anti-cancer drugs. While some HDACis have already been approved for therapy and others are in different phases of clinical trials, the exact mechanism of action of this drug class remains elusive. Previous studies have shown that HDACis cause massive changes in chromatin structure but only moderate changes in gene expression. To which extent these changes manifest at the protein level has never been investigated on a proteome-wide scale. Here, we have studied HDACi-treated cells by large-scale mass spectrometry based proteomics. We show that HDACi treatment affects primarily the nuclear proteome and induces a selective decrease of bromodomain containing proteins (BCPs), the main readers of acetylated histone marks. By combining time-resolved proteome and transcriptome profiling, we show that BCPs are affected at the protein level as early as 12 hours after HDACi treatment and that their abundance is regulated by a combination of transcriptional and post-transcriptional mechanisms. Using gene silencing, we demonstrate that the decreased abundance of BCPs is sufficient to mediate important transcriptional changes induced by HDACi. Our data reveals a new aspect of the mechanism of action of HDACi that is mediated by an interplay between histone acetylation and the abundance of BCPs.
Publication Title
Histone Deacetylase Inhibitors (HDACi) Cause the Selective Depletion of Bromodomain Containing Proteins (BCPs).
Sample Metadata Fields
Cell line, Treatment, Time
View Samples- Homo sapiens
- 8 Downloadable Samples
- Illumina HiSeq 2500
Description
In this study, we analyzed how non-coding double stranded RNA (dsRNAs) act as a damage associated molecular pattern (DAMP) in the skin, and how the human cathelicidin AMP LL-37 might influence growth factor production in response to this DAMP. Overall design: Each sample''s RNA was isolated form a single biological source of P6 NHEKs. In total there are 4 samples (non-replicates); Control (PBS treated), 1.75uM LL-37 treated, 0.1ug/ml Poly(I:C) treated, and co-treated with 1.75uM LL-37 and 0.1ug/ml Poly(I:C).
Publication Title
Non-coding Double-stranded RNA and Antimicrobial Peptide LL-37 Induce Growth Factor Expression from Keratinocytes and Endothelial Cells.
Sample Metadata Fields
Cell line, Treatment, Subject, Time
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
We examined the kinetics of production of mRNAs and small RNAs derived from transposable elements during mouse spermatogenesis, in whole gonads of wildtype and DNA methylation-deficient males (Dnmt3L and Miwi2 mutants). We found that in absence of DNA methylation, transposon reactivation is not constitutive but rather occurs in a class- and development-specific manner : both the intensity of reactivation and the number of reactivated transposon classes increased as germ cells progress in meiosis. Moreover, we observed that transposon silencing before meiosis is not due to increased cleavage by the piRNA machinery. In contrast, the burst of transposon transcripts occurring at meiosis in the absence of DNA methylation serve as substrates for increased piRNA production Overall design: Six whole testis samples were analyzed, corresponding to three time points (16.5dpc, 10dpp and 20dpp) each for Dnamt3L-/- animals and control littermates. For 16.5dpc, testes from 7/8 mice were pooled per genotype. For the other stages, three mice were pooled per genotype.
Publication Title
DNA methylation restrains transposons from adopting a chromatin signature permissive for meiotic recombination.
Sample Metadata Fields
No sample metadata fields
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