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SRP125111
Danio rerio
6 Downloadable Samples
NextSeq 500
Description
The short-lived turquoise killifish Nothobranchius furzeri (Nfu) is a valid model for aging studies. Here, we investigated its age-associated cardiac function. We observed oxidative stress accumulation and an engagement of microRNAs (miRNAs) in the aging heart. MiRNA-sequencing of 5 week (young), 12-21 week (adult) and 28-40 week (old) Nfu hearts revealed 23 up-regulated and 18 down-regulated miRNAs with age. MiR-29 family turned out as one of the most up-regulated miRNAs during aging. MiR-29 family increase induces a decrease of known targets like collagens and DNA methyl transferases (DNMTs) paralleled by 5´methyl-cytosine (5mC) level decrease. To further investigate miR-29 family role in the fish heart we generated a transgenic zebrafish model where miR-29 was knocked-down. In this model we found significant morphological and functional cardiac alterations and an impairment of oxygen dependent pathways by transcriptome analysis leading to hypoxic marker up-regulation. To get insights the possible hypoxic regulation of miR-29 family, we exposed human cardiac fibroblasts to 1% O2 levels. In hypoxic condition we found miR-29 down-modulation responsible for the accumulation of collagens and 5mC. Overall, our data suggest that miR-29 family up-regulation might represent an endogenous mechanism aimed at ameliorating the age-dependent cardiac damage leading to hypertrophy and fibrosis. Overall design: RNA was isolated from zebrafish heart samples (3 wt and 3 miR-29-sponge) and sequenced.
Publication Title
Age-dependent increase of oxidative stress regulates microRNA-29 family preserving cardiac health.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2000
Description
Muscle denervation due to injury, disease or aging results in impaired motor function. Restoring neuromuscular communication requires axonal regrowth and regeneration of neuromuscular synapses. Muscle activity inhibits neuromuscular synapse regeneration. The mechanism by which muscle activity regulates regeneration of synapses is poorly understood. Dach2 and Hdac9 are activity-regulated transcriptional co-repressors that are highly expressed in innervated muscle and suppressed following muscle denervation. Here, we report that Dach2 and Hdac9 inhibit regeneration of neuromuscular synapses. Importantly, we identified Myog and Gdf5 as muscle-specific Dach2/Hdac9-regulated genes that stimulate neuromuscular regeneration in denervated muscle. Interestingly, Gdf5 also stimulates presynaptic differentiation and inhibits branching of regenerating neurons. Finally, we found that Dach2 and Hdac9 suppress miR206 expression, a microRNA involved in enhancing neuromuscular regeneration. Overall design: RNAseq on innervated and 3 day denervated adult soleus muscle from wildtype mice is compared with that from 3 day denervated soleus muscle from Dach2/Hdac9 deleted mice to identify Dach2/Hdac9-regulated genes.
Publication Title
Dach2-Hdac9 signaling regulates reinnervation of muscle endplates.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 24 Downloadable Samples
- Illumina HiSeq 2000
Description
The heat shock response (HSR) is a mechanism to cope with proteotoxic stress by inducing the expression of molecular chaperones and other heat shock response genes. The HSR is evolutionarily well conserved and has been widely studied in bacteria, cell lines and lower eukaryotic model organisms. However, mechanistic insights into the HSR in higher eukaryotes, in particular in mammals, are limited. We have developed an in vivo heat shock protocol to analyze the HSR in mice and dissected heat shock factor 1 (HSF1)-dependent and -independent pathways. Whilst the induction of proteostasis-related genes was dependent on HSF1, the regulation of circadian function related genes, indicating that the circadian clock oscillators have been reset, was independent of its presence. Furthermore, we demonstrate that the in vivo HSR is impaired in mouse models of Huntington's disease but we were unable to corroborate the general repression of transcription after a heat shock found in lower eukaryotes. Overall design: RNA-Seq was performed on mRNA isolated from quadriceps femoris muscle of 24 mice. These mice were of wild type, R6/2, and Hsf1-/- genotypes. Two mice of each genotype were tested in four conditions: (1) heat shock, (2) control heat shock, (3) HSP90 inhibition (NVP-HSP990), and (4) HSP90 inhibition vehicle.
Publication Title
HSF1-dependent and -independent regulation of the mammalian in vivo heat shock response and its impairment in Huntington's disease mouse models.
Sample Metadata Fields
Age, Specimen part, Treatment, Subject
View Samples- Homo sapiens
- 15 Downloadable Samples
Illumina HumanHT-12 V4.0 expression beadchip
Description
The goal of this study was to assess whether the presence of HLA-B*35 contributes to activation of ER stress/UPR and inflammation in lcSScPAH PBMC.
Publication Title
The HLA-B*35 allele modulates ER stress, inflammation and proliferation in PBMCs from Limited Cutaneous Systemic Sclerosis patients.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 14 Downloadable Samples
- NextSeq 500
Description
Background: Here, the role of a-ketoglutarate (aKG) in the epi-metabolic control of DNA demethylation has been investigated in therapeutically relevant cardiac mesenchymal cells (CMSCs) isolated from controls and type 2 diabetes donors. Methods & results: Quantitative global analysis, methylated and hydroxymethylated DNA sequencing and gene specific GC methylation detection revealed an accumulation of 5mC, 5hmC and 5fC in the genomic DNA of human CMSCs isolated from diabetic (D) donors (D-CMSCs). Whole heart genomic DNA analysis revealed iterative oxidative cytosine modification accumulation in mice exposed to high fat diet (HFD), injected with streptozotocin (STZ) or both in combination (STZ-HFD). In this context, untargeted and targeted metabolomics indicated an intracellular reduction of aKG synthesis in D-CMSCs and in the whole heart of HFD mice. This observation was paralleled by a compromised thymine DNA glycosylase (TDG) and ten eleven translocation protein 1 (TET1) association and function with TET1 relocating out of the nucleus. Molecular dynamics and mutational analyses showed that aKG binds TDG on Arg275 providing an enzymatic allosteric activation. As a consequence, the enzyme significantly increased its capacity to remove G/T nucleotide mismatched or 5fC. Accordingly, an exogenous source of aKG restored the DNA demethylation cycle by promoting TDG function, TET1 nuclear localization and TET/TDG association. TDG inactivation by CRISPR/Cas9 knockout or TET/TDG siRNA knockdown induced 5fC accumulation thus partially mimicking the diabetic epigenetic landscape in cells of non- diabetic origin. The novel compound (S)-2-[(2,6-dichlorobenzoyl)amino]succinic acid (AA6), identified as an inhibitor of aKG-dehydrogenase, increased the aKG level in D- CMSCs and in the heart of HFD mice eliciting DNA demethylation, glucose uptake and insulin response. Conclusions: In this report we established that diabetes may epigenetically modify and compromise function of therapeutically relevant cardiac mesenchymal cells. Restoring the epi-metabolic control of DNA demethylation cycle promises beneficial effects on cells compromised by environmental metabolic changes. Overall design: Human primary cardiac mesenchymal cells (CMSC) from 7 diabetic (D) and 7 non-diabetic (ND) donors were analyzed after few rounds of ex vivo expansion. RNA was isolated and sequenced.
Publication Title
Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients: Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 20 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Gastric cancer is still one of the most common causes of cancer-related death worldwide, which is mainly attributable to late diagnosis and poor treatment options. Infection with H. pylori, different environmental factors and genetic alterations are known to influence the risk of developing gastric tumors. However, the molecular mechanisms involved in gastric carcinogenesis are still not fully understood, making it difficult to design targeted therapeutic approaches.
Publication Title
The stem cell factor SOX2 regulates the tumorigenic potential in human gastric cancer cells.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Time
View Samples- Mus musculus
- 158 Downloadable Samples
- Illumina HiSeq 2500
Description
Tissue resident macrophages are functionally diverse cells that share an embryonic mesodermal origin. However, the mechanism(s) that control their specification remain unclear. We performed transcriptional, molecular and in situ spatio-temporal analyses of macrophage development in mice. We report that Erythro-Myeloid Progenitors generate pre-macrophages (pMacs) that simultaneously colonize the head and caudal embryo from embryonic day (E)9.5 in a chemokine-receptor dependent manner, to further differentiate into tissue F4/80+ macrophages. The core macrophage transcriptional program initiated in pMacs, is rapidly diversified in early macrophages as expression of transcriptional regulators becomes tissue-specific. For example, the preferential expression of the transcriptional regulator Id3 initiated in early fetal liver macrophages appears critical for Kupffer cell differentiation, as inactivation of Id3 causes a selective Kupffer cell deficiency that persists in adults. We propose that colonization of developing tissues by differentiating macrophages is immediately followed by their specification as they establish residence, hereby generating the macrophage diversity observed in post-natal tissues. Overall design: RNA-sequencing of sorted macrophage cell populations (Mac) and progenitors (EMP, pMac) from various tissues and collected at different time points, including technical and biological replicates
Publication Title
Specification of tissue-resident macrophages during organogenesis.
Sample Metadata Fields
Specimen part, Subject, Time
View Samples- Mus musculus
- 4 Downloadable Samples
- Illumina HiSeq 1000
Description
We constructed a polycistronic lentiviral vector to overexpress 3 germ cell specific genes (Stella, Oct4 and Nanos2) in mouse embryonic fibroblast (MEFs) and evaluated the transcriptome portrait in partially reprogrammed cells.We sequenced RNA samples from bulk cell population of two biological duplicates of MEF-GFP (control) and MEF-SON (overexpressed) 21 days post infection. Differential expression analysis of 50 M pair-end read per samples showed overexpression of neurogenesis, blood vessel and proliferation related genes and downregulation of chondroitin sulphate metabolic process, nitric oxide production and innate immune response genes. Overall design: Examination of whole transcriptome following concurrent overexpression of Stella, Oct4 and Nanos2 in MEFs.
Publication Title
Suppression of dsRNA response genes and innate immunity following Oct4, Stella, and Nanos2 overexpression in mouse embryonic fibroblasts.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 1 Downloadable Sample
- Illumina HiSeq 1500
Description
Tissue resident macrophages are functionally diverse cells that share an embryonic mesodermal origin. However, the mechanism(s) that control their specification remain unclear. We performed transcriptional, molecular and in situ spatio-temporal analyses of macrophage development in mice. We report that Erythro-Myeloid Progenitors generate pre-macrophages (pMacs) that simultaneously colonize the head and caudal embryo from embryonic day (E)9.5 in a chemokine-receptor dependent manner, to further differentiate into tissue F4/80+ macrophages. The core macrophage transcriptional program initiated in pMacs, is rapidly diversified in early macrophages as expression of transcriptional regulators becomes tissue-specific. For example, the preferential expression of the transcriptional regulator Id3 initiated in early fetal liver macrophages appears critical for Kupffer cell differentiation, as inactivation of Id3 causes a selective Kupffer cell deficiency that persists in adults. We propose that colonization of developing tissues by differentiating macrophages is immediately followed by their specification as they establish residence, hereby generating the macrophage diversity observed in post-natal tissues. Overall design: RNA-sequencing of sorted macrophage cell populations (Mac) and progenitors (EMP, pMac) from various tissues and collected at different time points, including technical and biological replicates
Publication Title
Specification of tissue-resident macrophages during organogenesis.
Sample Metadata Fields
Specimen part, Subject, Time
View Samples- Homo sapiens
- 25 Downloadable Samples
Affymetrix Human Genome U219 Array (hgu219), Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
EphB2 Promotes Progression of Cutaneous Squamous Cell Carcinoma.
Sample Metadata Fields
Specimen part, Cell line
View Samples