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SRP201811
Homo sapiens
8 Downloadable Samples
Illumina HiSeq 2500
Description
Background: Degenerative disc disease (DDD) is a primary contributor to low back pain, a leading cause of disability. Progression of DDD is aided by inflammatory cytokines in the intervertebral disc (IVD), particularly TNF-a and IL-1ß, but current treatments fail to effectively target this mechanism. The objective of this study was to explore the feasibility of CRISPR epigenome editing based therapy for DDD, by modulation of TNFR1/IL1R1 signaling in pathological human IVD cells. Methods: Human IVD cells from the nucleus pulposus of patients receiving surgery for back pain were obtained and the regulation of TNFR1/IL1R1 signaling by a lentiviral CRISPR epigenome editing system was tested. These cells were tested for successful lentiviral transduction/expression of dCas9-KRAB system and regulation of TNFR1/IL1R1 expression. TNFR1/IL1R1 signaling disruption was investigated via measurement of NF-?B activity, apoptosis, and anabolic/catabolic changes in gene expression post inflammatory challenge. Results: CRISPR epigenome editing systems were effectively introduced into pathological human IVD cells and significantly downregulated TNFR1 and IL1R1. This downregulation significantly attenuated deleterious TNFR1 signaling but not IL1R1 signaling. This is attributed to less robust IL1R1 expression downregulation, and IL-1ß driven reversal of IL1R1 expression downregulation in a portion of patient IVD cells. Additionally, RNAseq data indicated a novel transcription factor targets, IRF1 and TFAP2C, as being a primary regulators of inflammatory signaling in IVD cells. Discussion: These results demonstrate the feasibility of CRISPR epigenome editing of inflammatory receptors in pathological IVD cells, but highlight a limitation in epigenome targeting of IL1R1. This method has potential application as a novel gene therapy for DDD, to attenuate the deleterious effect of inflammatory cytokines present in the degenerative IVD. Overall design: Patient nucleus pulposus cells (TNFR1kd and nontargeting control) were analyzed by RNA-seq with and without TNF-a treatment.
Publication Title
Lentiviral CRISPR Epigenome Editing of Inflammatory Receptors as a Gene Therapy Strategy for Disc Degeneration.
Sample Metadata Fields
Sex, Age, Specimen part, Treatment, Subject
View Samples- Homo sapiens
- 28 Downloadable Samples
Illumina HumanMethylation27 BeadChip (HumanMethylation27_270596_v.1.2), Illumina HumanHT-12 V4.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Brain transcriptional and epigenetic associations with autism.
Sample Metadata Fields
Age, Specimen part, Disease, Disease stage, Subject
View Samples- Homo sapiens
- 28 Downloadable Samples
- Illumina HumanMethylation27 BeadChip (HumanMethylation27_270596_v.1.2), Illumina HumanHT-12 V4.0 expression beadchip
Description
Autism is a common neurodevelopmental syndrome. Numerous rare genetic etiologies are reported; most cases are idiopathic. To uncover important gene dysregulation in autism we analyzed carefully selected idiopathic autistic and control cerebellar and BA19 (occipital) brain tissues using high resolution whole genome gene expression and DNA methylation microarrays. No changes in DNA methylation were identified in autistic brain but gene expression abnormalities in two areas of metabolism were apparent: down-regulation of genes of mitochondrial oxidative phosphorylation and of protein translation. We also found associations between specific behavioral domains of autism and specific brain gene expression modules related to myelin/myelination, inflammation/immune response and purinergic signaling. This work highlights two largely unrecognized molecular pathophysiological themes in autism and suggests differing molecular bases for autism behavioral endophenotypes.
Publication Title
Brain transcriptional and epigenetic associations with autism.
Sample Metadata Fields
Age
View Samples- Mus musculus
- 22 Downloadable Samples
- Illumina HiSeq 2500
Description
Calorie restriction (CR) enhances longevity and mitigates aging phenotypes in numerous species. Physiological responses to CR are cell-type specific and variable throughout the lifespan; however, the mosaic of molecular changes responsible CR benefits remain unclear, particularly in brain regions susceptible to deterioration throughout aging. Thus, we examined the influence of long-term CR on the CA1 hippocampal region, a key learning and memory brain area that is vulnerable to age-related pathologies, such as Alzheimer’s disease (AD). Through mRNA sequencing and NanoString nCounter analysis, we demonstrate that one year of CR feeding suppresses an age-dependent signature of 882 genes functionally associated with synaptic transmission-related pathways, including calcium signaling, long-term potentiation (LTP), and Creb signaling in wild-type mice. By comparing the influence of CR on hippocampal CA1 region transcriptional profiles at younger- (5 months) and older-adult (15 months) timepoints, we identify conserved upregulation of proteome quality control and calcium buffering genes, including heat shock 70 kDa proteins 1b and 5 (Hspa1b and Hspa5), protein disulfide isomerase family A members 4 and 6 (Pdia4 and Pdia6), and calreticulin (Calr). Expression levels of putative neuroprotective factors, klotho (Kl) and transthyretin (Ttr), are also elevated by CR throughout adulthood, although the global CR-specific expression profiles at young and older timepoints are highly divergent. At a previously unachieved resolution, our results demonstrate conserved activation of neuroprotective gene signatures and broad CR-suppression of age-dependent hippocampal CA1 region expression changes, indicating that CR functionally maintains a more youthful transcriptional state within hippocampal CA1 throughout aging. Overall design: Hippocampal CA1 region mRNA profiles of younger- (5 months) and older-adult (15 months) mice on calorie-restricted (CR) and normal (AD) diets were generated by deep sequencing using Illumina HiSeq 2500.
Publication Title
Calorie Restriction Suppresses Age-Dependent Hippocampal Transcriptional Signatures.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 8 Downloadable Samples
Affymetrix Human Genome U133A Array (hgu133a)
Description
The normal growth and function of mammary epithelial cells depend on interactions with the supportive stroma. Alterations in this communication can lead to the progression or expansion of malignant growth. The human mammary gland contains two distinctive types of fibroblasts within the stroma. The epithelial cells are surrounded by loosely connected intralobular fibroblasts, which are subsequently surrounded by the more compacted interlobular fibroblasts. The different proximity of these fibroblasts to the epithelial cells suggests distinctive functions for these two subtypes. In this report, we compared the gene expression profiles between the two stromal subtypes.
Publication Title
Interlobular and intralobular mammary stroma: genotype may not reflect phenotype.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 2886 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Consider the problem of designing a panel of complex biomarkers to predict a patient's health or disease state when one can pair his or her current test sample, called a target sample, with the patient's previously acquired healthy sample, called a reference sample. As contrasted to a population averaged reference, this reference sample is individualized. Automated predictor algorithms that compare and contrast the paired samples to each other could result in a new generation of test panels that compare to a person's healthy reference to enhance predictive accuracy. This study develops such an individualized predictor and illustrates the added value of including the healthy reference for design of predictive gene expression panels. The objective is to predict each subject's state of infection, e.g., neither exposed nor infected, exposed but not infected, pre-acute phase of infection, acute phase of infection, post-acute phase of infection. Using gene microarray data collected in a large-scale serially sampled respiratory virus challenge study, we quantify the diagnostic advantage of pairing a person's baseline reference with his or her target sample.
Publication Title
An individualized predictor of health and disease using paired reference and target samples.
Sample Metadata Fields
Specimen part, Subject, Time
View Samples- Mus musculus, Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Full title: Prepubertal Human Spermatogonia and Mouse Gonocytes Share Conserved Gene Expression of Germline Stem Cell Regulatory Molecules
Publication Title
Prepubertal human spermatogonia and mouse gonocytes share conserved gene expression of germline stem cell regulatory molecules.
Sample Metadata Fields
Age
View Samples- Homo sapiens
- 132 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Venous thromboembolism (VTE) is a major cause of morbidity and mortality. Pulmonary embolism is a life threatening manifestation of VTE that occurs in at least half the patients on presentation. In addition, VTE recurs in up to 30% of patients after a standard course of anticoagulation, and there is not a reliable way of predicting recurrence. We investigated whether gene expression profiles of whole blood could distinguish patients with VTE from healthy controls, single VTE from those with recurrence, and DVT alone from those with PE. 70 adults with VTE on warfarin and 63 healthy controls were studied. Patients with antiphospholipid syndrome or cancer were excluded. Blood was collected in PAXgene tubes, RNA isolated, and gene expression profiles obtained using Affymetrix arrays. We developed a 50 gene model that distinguished healthy controls from subjects with VTE with excellent receiver operating characteristics (AUC 0.94; P < 0.0001). We also discovered a separate 50 gene model that distinguished subjects with a single VTE from those with recurrent VTE with good receiver operating characteristics (AUC 0.75; P=0.008). In contrast, we were unable to distinguish subjects with DVT from those with PE using gene expression profiles. Gene expression profiles of whole blood can distinguish subjects with VTE from healthy controls and subjects with a single VTE from those with recurrence. Additional studies should be performed to validate these results and develop diagnostic tests. Gene expression profiling is likely translatable to other thrombotic disorders(e.g., patients with cancer and VTE).
Publication Title
Whole blood gene expression analyses in patients with single versus recurrent venous thromboembolism.
Sample Metadata Fields
Sex, Age, Race
View Samples- Homo sapiens
- 10 Downloadable Samples
- Illumina HiSeq 2000
Description
Purpose: RNA-Seq analysis can help identify large set of differentially expressed genes at a time. We performed RNA-Seq analysis to identify differentially expressed genes in the PBMCs of war veterans suffering from PTSD. Methods: Total RNA from PBMCs from PTSD +ve and -ve individuals were used for RNA-Seq analysis. Results: We obtained, on average, ~60 millions reads per sample. More than 70% of the reads were mapped to human genome. Functional analysis of the differentially expressed genes (362) revealed dysregulation in immune system network. Conclusions: Our present study provides further proof that immune system related genes and pathways are dysregulated in PTSD PBMCs. Overall design: RNA-Seq was performed with RNA from 5 each control and PTSD individuals. PBMCs collected within one hour of blood draw were used for RNA isolation. 1 ug of total RNA was used for library synthesis and sequenced in a HighSeq 2000 illumina instrument at Tufts University.
Publication Title
Decreased AGO2 and DCR1 in PBMCs from War Veterans with PTSD leads to diminished miRNA resulting in elevated inflammation.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 35 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The role of the beta2 adrenergic receptor (2AR) after stroke is unclear as pharmacological manipulations of the 2AR have produced contradictory results. We previously showed that mice deficient in the 2AR (2KO) had smaller infarcts compared to wild-type mice (FVB) after middle cerebral artery occlusion (MCAO), a model of stroke. To elucidate mechanisms of this neuroprotection, we evaluated changes in gene expression using microarrays comparing differences before and after MCAO, and differences between genotypes. Genes associated with inflammation and cell death were enriched after MCAO in both genotypes, and we identified several genes not previously shown to increase following ischemia (Ccl9, Gem, and Prg4). In addition to networks that were similar between genotypes, one network with a central node of G protein-coupled receptor and including biological functions carbohydrate metabolism, small molecule biochemistry and inflammation was identified in FVB mice but not in 2KO mice. Analysis of differences between genotypes revealed 11 genes differentially expressed by genotype in all conditions. We demonstrate greater Glo1 protein levels and lower Pmaip/Noxa mRNA levels in 2KO mice. As both genes are implicated in NFB signaling, we measured p65 activity and tumor necrosis factor alpha (TNF) levels 24h after MCAO. MCAO-induced p65 activation and post-ischemic TNF production were both greater in FVB compared to 2KO mice. These results suggest that loss of 2AR signaling results in a neuroprotective phenotype in part due to decreased NFB signaling, decreased inflammation, and decreased apoptotic signaling in the brain.
Publication Title
Mice lacking the β2 adrenergic receptor have a unique genetic profile before and after focal brain ischaemia.
Sample Metadata Fields
Sex, Specimen part
View Samples