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accession-icon SRP068733
HDAC inhibitor SAHA reverses inflammatory gene expression in diabetic endothelial cells
  • organism-icon Homo sapiens
  • sample-icon 30 Downloadable Samples
  • Technology Badge IconIlluminaHiSeq2500

Description

While histone deacetylase (HDAC) inhibitors are thought to regulate gene expression by post-translational modification of histone as well as non-histone proteins. While histone hyperacetylation has long been considered the paradigmatic mechanism of action, recent genome-wide profiles indicate more complex interactions with the epigenome. In particular, HDAC inhibitors also induce histone deacetylation at the promoters of highly active genes, resulting in gene suppression. This was linked to the loss of histone acetyltransferase (HAT) binding. To illustrate pre-clinical utility of the HDAC inhibitor SAHA as a therapeutic, we show reversal of diabetes-associated EP300 target genes in diabetic HAECs of primary origin. These results were confirmed using SAHA, C646 (EP300/CREBBP inhibitor) or EP300 siRNA. These findings suggest the inhibition of gene expression by SAHA is mediated by EP300 function and provide a rationale for clinical trials of safety and efficacy in patients with diabetes. Overall design: Human aortic endothelial cells from a diabetic and non-diabetic individual were stimulated with DMSO (control), SAHA (2 µM, HDAC inhibitor) or C646 (10 µM, EP300 inhibitor) for 12 hours, or EP300 siRNA or non-target siRNA (control) for 4 hours, followed by 48 hours in fresh media. Study performed in triplicate.

Publication Title

Systems approach to the pharmacological actions of HDAC inhibitors reveals EP300 activities and convergent mechanisms of regulation in diabetes.

Alternate Accession IDs

GSE77108

Sample Metadata Fields

No sample metadata fields

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accession-icon SRP096177
Deep sequencing reveals novel Set7 networks
  • organism-icon Homo sapiens
  • sample-icon 6 Downloadable Samples
  • Technology Badge IconIllumina Genome Analyzer IIx

Description

Methyl-dependent regulation of transcription has expanded from a traditional focus on histones to encompass transcription factor modulation. While the Set7 lysine methyltransferase is associated with pro-inflammatory gene expression in vascular endothelial cells, genome-wide regulatory roles remain to be investigated. From initial characterization of Set7 as specific for methyl-lysine 4 of H3 histones (H3K4m1), biochemical activity toward non-histone substrates has revealed additional mechanisms of gene regulation. mRNA-Seq revealed transcriptional deregulation of over 8,000 genes in an endothelial model of Set7 knockdown. Gene ontology identified up-regulated pathways involved in developmental processes and extracellular matrix remodeling, whereas pathways regulating the inflammatory response as well as nitric oxide signaling were down-regulated. Chromatin maps derived from ChIP-Seq profiling of H3K4m1 identified several hundred loci with loss of H3K4m1 at gene regulatory elements associated with an unexpectedly subtle effect on gene expression. Transcription factor network analysis implicated six previously described Set7 substrates in mRNA-Seq changes, and we predict that Set7 post-translationally regulates other transcription factors associated with vascular endothelial gene expression through the presence of Set7 amino acid methylation motifs. We describe a role for Set7 in regulating developmental pathways and response to stimuli (inflammation/immune response) in human endothelial cells of vascular origin. Set7-dependent gene expression changes that occurred independent of H3K4m1 may involve transcription factor lysine methylation events. The method of mapping measured transcriptional changes to transcription factors to identify putative substrates with strong associations to functional changes is applicable to substrate prediction for other broad-substrate histone modifiers. Overall design: We used lentiviral delivered shRNA to knock down the expression of Set7 protein in HMEC-1 cells. As a control, we used a non-targeting shRNA. RNA-seq was performed in biological triplicate. Set7 knock down datasets are labeled “Set7KD” and non-targeting control datasets are labeled “NTC”

Publication Title

Deep sequencing reveals novel Set7 networks.

Alternate Accession IDs

GSE93236

Sample Metadata Fields

Cell line, Subject

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accession-icon SRP028727
Maternal overnutrition causes insulin resistance and alters skeletal muscle oxidative phosphorylation in adult rat offspring
  • organism-icon Rattus norvegicus
  • sample-icon 11 Downloadable Samples
  • Technology Badge IconIllumina Genome Analyzer IIx

Description

Maternal obesity can program metabolic syndrome in offspring but the mechanisms are not well characterized. Moreover, the consequences of maternal overnutrition in the absence of frank obesity remain poorly understood. This study aimed to determine the effects of maternal consumption of a high fat-sucrose diet on the skeletal muscle metabolic and transcriptional profiles of adult offspring. Female Sprague Dawley rats were fed either a diet rich in saturated fat and sucrose (HFD, 23.5% fat, 20% sucrose wt/wt) or a standard chow diet (NFD, 7% fat, 10% sucrose w/w) for the 3 weeks prior to mating and throughout pregnancy and lactation. Although maternal weights were not different between groups at conception or weaning, HFD dams were ~22% heavier than chow fed dams from mid-pregnancy until 4 days post-partum. Adult male offspring of HFD dams were not heavier than controls but demonstrated features of insulin resistance including elevated plasma insulin concentration (+40%, P<0.05). Next Generation mRNA Sequencing was used to identify differentially expressed genes in the soleus muscle of offspring, and Gene Set Enrichment Analysis (GSEA) to detect coordinated changes that are characteristic of a biological function. GSEA identified 15 pathways enriched for up-regulated genes, including cytokine signaling (P<0.005), starch and sucrose metabolism (P<0.017), and inflammatory response (P<0.024). A further 8 pathways were significantly enriched for down-regulated genes including oxidative phosphorylation (P<0.004) and electron transport (P<0.022). Western blots confirmed a ~60% reduction in the phosphorylation of the insulin signaling protein Akt (P<0.05) and ~70% reduction in mitochondrial complexes II (P<0.05) and V expression (P<0.05). On a normal diet, offspring of HFD dams developed an insulin resistant phenotype, with transcriptional evidence of muscle cytokine activation, inflammation and mitochondrial dysfunction. These data indicate that maternal overnutrition, even in the absence of pre-pregnancy obesity can promote metabolic dysregulation and predispose offspring to type 2 diabetes. Overall design: Messenger RNA profile of skeletal muscle of male offspring from female Sprague Dawley rats fed either a diet rich in saturated fat and sucrose (HFD, 23.5% fat, 20% sucrose wt/wt) or a standard chow diet (NFD, 7% fat, 10% sucrose w/w) for the 3 weeks prior to mating and throughout pregnancy and lactation. There were 5 HFD samples compared to 6 NFD control samples.

Publication Title

Maternal overnutrition programs changes in the expression of skeletal muscle genes that are associated with insulin resistance and defects of oxidative phosphorylation in adult male rat offspring.

Alternate Accession IDs

GSE49797

Sample Metadata Fields

No sample metadata fields

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accession-icon SRP101460
Multicellular Transcriptional Analysis of Mammalian Heart Regeneration
  • organism-icon Mus musculus
  • sample-icon 127 Downloadable Samples
  • Technology Badge IconIllumina HiSeq 2500

Description

The inability of the adult mammalian heart to regenerate following injury represents a major barrier in cardiovascular medicine. In contrast, the neonatal mammalian heart retains a transient capacity for regeneration, which is lost shortly after birth. Defining the molecular mechanisms that govern regenerative capacity in the neonatal period remains a central goal in cardiac biology. Here, we construct a transcriptional atlas of multiple cardiac cell populations, which enables comparative analyses of the regenerative (neonatal) versus non-regenerative (adult) state for the first time. This work provides a comprehensive transcriptional resource of multiple cardiac cell populations during cardiac development, repair and regeneration. Our findings define a transcriptional program underpinning the neonatal regenerative state and identifies an epigenetic barrier to re-induction of the regenerative program in adult cardiomyocytes. Overall design: Cardiomyocytes, fibroblasts, leukocytes and endothelial cells from infarcted and non-infarcted neonatal (P1) and adult (P56) hearts were isolated by enzymatic dissociation and FACS. RNA sequencing (RNA-seq) was performed on these cell populations to generate a transcriptomic atlas of the major cardiac cell populations during cardiac development, repair and regeneration. In addition, we surveyed the epigenetic landscape of cardiomyocytes during post-natal maturation by performing deep sequencing of accessible chromatin regions using the Assay for Transposase-Accessible Chromatin (ATAC-seq) from purified cardiomyocyte nuclei (P1, P14 and P56).

Publication Title

Multicellular Transcriptional Analysis of Mammalian Heart Regeneration.

Alternate Accession IDs

GSE95755

Sample Metadata Fields

Specimen part, Treatment, Subject

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accession-icon SRP045149
Genome-wide DNA methylation analysis reveals dynamic changes in the cardiac methylome during post-natal heart development (RNA-Seq)
  • organism-icon Mus musculus
  • sample-icon 6 Downloadable Samples
  • Technology Badge IconIllumina Genome Analyzer IIx

Description

Epigenetic modifications have emerged as central players in the coordination of gene expression networks during cardiac development. While several studies have investigated the role of histone modifications during heart development, relatively little is known about the role of DNA methylation. The purpose of the current study was to determine whether DNA methylation plays an important role in guiding transcriptional changes during the neonatal period, which is an important developmental window for cardiac maturation and cardiomyocyte cell cycle arrest. We used methyl binding domain protein sequencing (MBD-seq) and mRNA-seq to profile DNA methyation and gene expression respectively in neonatal hearts at P1 and P14 stages. Thousands of differentially methylated regions (DMRs) were identified between P1 and P14, the vast majority of which were hypermethylated. Gene ontology analysis revealed that these hypermethylated genes were associated with transcriptional regulation of important developmental signaling pathways, including Hedgehog, BMP, TGF beta, FGF and Wnt/b-catenin signaling. A significant enrichment for myogenic transcription factors and Smad2/3/4 binding sites was also noted among differentially methylated peaks at P14. This study provides novel evidence for widespread alterations in DNA methylation during post-natal heart maturation and suggests that DNA methylation plays an important role in cardiomyocyte cell cycle arrest during the neonatal period. Overall design: mRNA-seq to profile gene expression in neonatal hearts at P1 and P14 stages (post-natal day 1 and 14 respectively) in three biological replicates.

Publication Title

Dynamic changes in the cardiac methylome during postnatal development.

Alternate Accession IDs

GSE59970

Sample Metadata Fields

No sample metadata fields

View Samples
accession-icon SRP066667
Etiology matters - Comparing Genomic DNA Methylation Patterns in Three Rat Models of Acquired Epilepsy (Amygdala stimulation – mRNA-seq)
  • organism-icon Rattus norvegicus
  • sample-icon 10 Downloadable Samples
  • Technology Badge IconIllumina Genome Analyzer IIx

Description

Explore DNA methylation in focal amygdala stimulation model of epilepsy and its relationship to gene expression. Overall design: Examination of expression changes in stimulated rats compared to sham operated animals in focal amygdala stimulation model of epilpesy.

Publication Title

Etiology matters - Genomic DNA Methylation Patterns in Three Rat Models of Acquired Epilepsy.

Alternate Accession IDs

GSE75402

Sample Metadata Fields

No sample metadata fields

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accession-icon GSE69659
Maize death acids, 9-lipoxygenase derived cyclopente(a)nones, display activity as cytotoxic phytoalexins and transcriptional mediators
  • organism-icon Zea mays
  • sample-icon 6 Downloadable Samples
  • Technology Badge Icon Affymetrix Maize Genome Array (maize)

Description

Plant damage promotes the interaction of lipoxygenases (LOX) with fatty acids yielding 9-hydroperoxides, 13-hydroperoxides and complex arrays of oxylipins. The action of 13-LOX on linolenic acid enables production of 12-oxo-phytodienoic acid (12-OPDA) and its downstream products, termed jasmonates. As signals, jasmonates have related yet distinct roles in the regulation of plant resistance against insect and pathogen attack. A similar pathway involving 9-LOX activity on linolenic and linoleic acid leads to the 12-OPDA positional isomer, 10-oxo-11-phytodienoic acid (10-OPDA) and 10-oxo-11-phytoenoic acid (10-OPEA), respectively; however, physiological roles for 9-LOX cyclopentenones have remained unclear. In developing maize (Zea mays) leaves, southern leaf blight (Cochliobolus heterostrophus) infection results in dying necrotic tissue and the localized accumulation of 10-OPEA, 10-OPDA and a series of related 14- and 12-carbon metabolites, collectively termed death acids. 10-OPEA accumulation becomes wound-inducible within fungal-infected tissues and at physiologically relevant concentrations acts as a phytoalexin by suppressing the growth of fungi and herbivores including Aspergillus flavus, Fusarium verticillioides, and Helicoverpa zea. Unlike previously established maize phytoalexins, 10-OPEA and 10-OPDA display significant phytotoxicity. Both 12-OPDA and 10-OPEA promote the transcription of defense genes encoding glutathione S-transferases, cytochrome P450s, and pathogenesis-related proteins. In contrast, 10-OPEA only weakly promotes the accumulation of multiple protease inhibitor transcripts. Consistent with a role in dying tissue, 10-OPEA application promotes cysteine protease activation and cell death which is inhibited by overexpression of the cysteine protease inhibitor maize cystatin-9. Functions for 10-OPEA and associated death acids are consistent with specialized roles in local defense reactions.

Publication Title

Maize death acids, 9-lipoxygenase-derived cyclopente(a)nones, display activity as cytotoxic phytoalexins and transcriptional mediators.

Alternate Accession IDs

E-GEOD-69659

Sample Metadata Fields

Specimen part

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accession-icon GSE769
CF vs control Pancreas
  • organism-icon Mus musculus
  • sample-icon 6 Downloadable Samples
  • Technology Badge Icon Affymetrix Murine Genome U74A Version 2 Array (mgu74av2)

Description

Total RNA was prepared using TRIzol reagent from the pancreata of eight week old male mice. The genotypes were Control: gastrin+/-, CFTR+/+; and CF: gastrin+/-, CFTR-/-. All mice were on 95% black6, 5% 129Sv background. Mice were fed Peptamen from age 10 days to prevent intestinal obstruction.

Publication Title

Acidic duodenal pH alters gene expression in the cystic fibrosis mouse pancreas.

Alternate Accession IDs

E-GEOD-769

Sample Metadata Fields

No sample metadata fields

View Samples
accession-icon GSE28059
Expression in Huh7 cells 72 hours after treatment with scramble, SPTLC123, or DEGS siRNA
  • organism-icon Homo sapiens
  • sample-icon 8 Downloadable Samples
  • Technology Badge Icon Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)

Description

Dysregulation of ceramide synthesis has been associated with metabolic disorders such as atherosclerosis and diabetes mellitus. Using a human hepatoma cell line (Huh7), we investigated the changes in lipid homeostasis and gene expression when the synthesis of ceramide is perturbed by knocking down serine transferases subunits 1, 2 and 3 (SPTLC123) or dihydroceramide desaturase (DEGS1). While the inhibition of serine palmitoyl transferase (SPTLC) affects ceramide production differently at the subspecies level depending upon which SPTLC subunit is silenced; depleting DEGS1 is sufficient to produce a similar outcome as knocking down all SPTLC subunits. Both the distribution of multiple lipid classes, especially at the subspecies level, and the global transcriptional profile is altered differently when either SPTLC123 or DEGS1 were silenced. The overall transcriptional changes indicate a negative regulation in biosynthetic processes and a down-regulation of genes involved in general endomembrane trafficking for both DEGS1 and SPTLC123 siRNA treated cells, but also the up-regulation of genes involved with cell migration function in DEGS1 siRNA cells. Pathway analysis indicate changes in amino acid, sugar and nucleotide metabolisms as well as vesicle trafficking between organelles occurred more robustly in DEGS1 silenced cells. Although either SPTLC123 or DEGS1 siRNA treatment positively regulated numerous genes involved with endocytosis and endosomal recycling, depleting SPTLC123 caused transcriptional changes in genes primarily involved with lipid metabolism. The alterations reflect how SPTLC or DEGS1 silenced cells respond differently to disruption in lipid flux, but also maintain cellular lipid pools through increasing endocytotic processes and down-regulating metabolic biosynthesis without developing endoplasmic reticulum stress. Also, these results are the first to demonstrate that reducing ceramide synthesis by decreasing the function of either SPTLC or DEGS1 affects cellular function differently at the level of lipid synthesis and gene expression.

Publication Title

Silencing of enzymes involved in ceramide biosynthesis causes distinct global alterations of lipid homeostasis and gene expression.

Alternate Accession IDs

E-GEOD-28059

Sample Metadata Fields

Cell line

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accession-icon GSE51296
HDAC inhibitors attenuate the development of hypersensitivity in models of neuropathic pain
  • organism-icon Rattus norvegicus
  • sample-icon 16 Downloadable Samples
  • Technology Badge Icon Affymetrix Rat Gene 1.0 ST Array (ragene10st)

Description

This SuperSeries is composed of the SubSeries listed below.

Publication Title

HDAC inhibitors attenuate the development of hypersensitivity in models of neuropathic pain.

Alternate Accession IDs

E-GEOD-51296

Sample Metadata Fields

Specimen part

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refine.bio is a repository of uniformly processed and normalized, ready-to-use transcriptome data from publicly available sources. refine.bio is a project of the Childhood Cancer Data Lab (CCDL)

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Cite refine.bio

Casey S. Greene, Dongbo Hu, Richard W. W. Jones, Stephanie Liu, David S. Mejia, Rob Patro, Stephen R. Piccolo, Ariel Rodriguez Romero, Hirak Sarkar, Candace L. Savonen, Jaclyn N. Taroni, William E. Vauclain, Deepashree Venkatesh Prasad, Kurt G. Wheeler. refine.bio: a resource of uniformly processed publicly available gene expression datasets.
URL: https://www.refine.bio

Note that the contributor list is in alphabetical order as we prepare a manuscript for submission.

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