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SRP090566
Mus musculus
6 Downloadable Samples
Illumina HiSeq 2000
Description
The histone deacetylase HDAC2, which negatively regulates neuronal plasticity and synaptic gene expression, is upregulated both in Alzheimer’s disease (AD) patients and mouse models (Graff et al., 2012). Therapeutics targeting HDAC2 are speculated to be a promising avenue for ameliorating AD related cognitive impairment. However, attempts to generate HDAC2-specific inhibitors have not been successful. Here, we take a novel approach utilizing integrative genomics to identify proteins that mediate HDAC2 recruitment to synaptic plasticity genes. Functional screening revealed that knockdown of the transcription factor Sp3 phenocopied HDAC2 knockdown, and that Sp3 facilitated the recruitment of HDAC2 to synaptic genes. Importantly, like HDAC2, Sp3 expression was elevated in AD patients and mouse models, where Sp3 knockdown ameliorated synaptic dysfunction. Furthermore, exogenous expression of an HDAC2 fragment containing the Sp3 binding domain fully restored synaptic plasticity and memory in a mouse model with severe neurodegeneration. Our findings indicate that targeting the HDAC2-Sp3 complex could enhance synaptic and cognitive function, without affecting HDAC2 function in other processes. Overall design: We profiled gene expression levels in primary neurons treated with HDAC2 or Sp3 shRNAs through RNA-Seq to examine whether HDAC2 and Sp3 cooperatively regulate a set of genes.
Publication Title
The Transcription Factor Sp3 Cooperates with HDAC2 to Regulate Synaptic Function and Plasticity in Neurons.
Sample Metadata Fields
Specimen part, Treatment, Subject
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2000
Description
Gamma oscillations (20-50Hz) are a common local field potential signature in many brain regions that are generated by a resonant circuit between fast-spiking parvalbumin (PV)-positive interneurons and pyramidal cells. Changes in the magnitude and frequency of gamma have been observed in several neuropsychiatric disorders. However, it is unclear how disruptions in gamma oscillations affect cellular pathologies seen in these disorders. Here, we investigate this using the 5XFAD mouse model of Alzheimer’s disease (AD) and find reduced power and magnitude of behaviorally driven gamma oscillatory activity — even before the onset of plaque formation or measurable cognitive decline. Because of the early onset, we aimed to determine if exogenous manipulations of gamma could influence the progression of disease pathology. We find that driving PV-positive neurons at gamma frequency (40Hz) using channelrhodopsin-2 reduced total levels of amyloid-ß (Aß) 40 and 42 isoforms in the hippocampus of 5XFAD mouse. Driving PV-positive neurons at other frequencies, or driving excitatory neurons, did not reduce Aß levels. Furthermore, driving PV-positive neurons reduced enlarged endosomes in hippocampal neurons and cleavage intermediates of APP in 5XFAD mouse. Gene expression profiling revealed a neuroprotective response with morphological transformation of microglia and markedly increased phagocytosis of Aß by microglia. Inspired by these observations, we designed a non-invasive light-flickering paradigm that drives 40Hz gamma activity in mouse visual cortex. The light-flickering paradigm profoundly reduced Aß40 and Aß42 levels in the visual cortex of pre-symptomatic mice and greatly mitigated plaque load in the visual cortex of aged, symptomatic mice. This reduction was completely blocked by a GABA-A antagonist, providing further support for an essential role of GABAergic signaling in mediating neuroprotective gamma activity. Overall, our findings uncover a dramatic and previously unappreciated function of the brain’s endogenous gamma rhythms in reducing the production and increasing the clearance of Aß peptides, whose accumulation is believed to drive the pathogenesis of AD. Overall design: Two to four weeks following virus injection and implant placement, hippocampal CA1 neurons were optigenetically manipulated. During the experiment, 1mW of optical stimulation was delivered for 1h using a 40Hz stimulation protocol.
Publication Title
Gamma frequency entrainment attenuates amyloid load and modifies microglia.
Sample Metadata Fields
Age, Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 31 Downloadable Samples
- Illumina HiSeq 2500
Description
We report a pilot investigation for poly-A RNAs differentially expressed during Mycobacterium tuberculosis infection. Participation in this investigation from March 2010 to July 2013 was voluntary, only subjects that were >18 years old and that informed written consent were considered eligible. The recruitment of tuberculosis (TB) patients was done at public hospitals in Rio de Janeiro, Brazil. The diagnostic criteria for active pulmonary tuberculosis was at least one AFB (acid-fast bacilli) -positive sputum sample for M. tuberculosis and/or positive sputum culture and/or compatible clinical evolution for pulmonary TB and less than 15 days of anti-TB treatment and was in accordance with those of the Brazilian Ministry of Health. Blood was collected from recent close contacts (rCt) and active tuberculosis (TB) index cases (n=6). Latent TB infection (LTBI) was accessed by both tuberculin skin test (TST, cut-off = 5mm) and in house interferon-gamma release assays (IGRA, cut-off = 100 pg/ml), therefore, 12 rCt were classified as uninfected controls and 16 with LTBI. Subsequently, the sequencing was performed following the standard protocols on Illumina HiSeq® 2500 Sequencing System (Illumina, San Diego, CA) running 100 bp paired-end reads (PE100) and generating approximately 30 million reads passing filter for each sample to produce the mRNA reads. Mining these RNAseq data, highly prominent modulation of DOCK9, EPHA4, and NPC2 mRNA expression was observed in the TB samples, indicating that they might have a role in TB pathogenesis. These differential modulations upon M. Tuberculosis infection were further validated by additional evidences in larger cohorts from different geographical areas. Overall design: We collected blood samples from the recent close contacts (rCt) at the recruitment and monitored them for 1-year. All TB participants were treatment-naïve. An infection mRNA signature was derived from whole blood RNA sequencing data by comparing TB and uninfected rCt. We selected the 3 most prominent genes, by area under the ROC curve analysis, for additional validations. Some of the LTBI participants also showed the mRNA infection profile.
Publication Title
Transcriptomic Biomarkers for Tuberculosis: Evaluation of <i>DOCK9. EPHA4</i>, and <i>NPC2</i> mRNA Expression in Peripheral Blood.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 68 Downloadable Samples
- Illumina HiSeq 2500
Description
Rett syndrome (RTT) is a severe neurodevelopmental disorder that is caused by mutations in the gene methyl-CpG-binding-protein-2 (MECP2). However, the molecular mechanism by which these mutations mediate the RTT neuropathology remains enigmatic. In this study, we stimulated MeCP2-null cortical neurons (in vitro) and brains (in vivo) of a RTT mouse model to explore the effect of the loss of MeCP2 function on the activity-dependent transcriptomes of the cortex and hippocampus, respectively, using RNA-seq. These analyses revealed that the loss of MeCP2 results in aberrant global pattern of gene expression, characterized predominantly by higher levels of expression of activity-dependent genes, and anomalous alternative splicing events, specifically in response to neuronal activity. Overall design: For in vitro experiments, RNA-seq was performed on MeCP2-null (MT) and wild-type (WT) neuron-enriched cortical cultures that were either treated (T) with KCl for 3hr or not treated (N), after 10 days in culture. For in vivo experiments, RNA-seq was performed on hippocampi of MeCP2-null (MT) and wild-type (WT) mice that were either treated with kainic acid for 40 or 68 minutes, or not treated.
Publication Title
Activity-dependent aberrations in gene expression and alternative splicing in a mouse model of Rett syndrome.
Sample Metadata Fields
Specimen part, Treatment, Subject, Time
View Samples- Homo sapiens
- 10 Downloadable Samples
Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
We examined the biological effects of a potent second-generation proteasome inhibitor, ixazomib, in T-cell lymphoma and Hodgkin lymphoma cell lines and human xenograft models. Ixazomib resulted in time- and dose-dependent cytotoxicity and apoptosis in all cell lines (IC50s <75nM). In vivo studies via SCID tumor xenografts showed significant inhibition of tumor growth (P<0.001) with significantly improved survival (P<0.001) in Jurkat and L540 models with ixazomib-treated mice versus controls. Through global transcriptome and network analyses, ixazomib-treated Jurkat and L540 cells showed significant overlap in biological functions involved in regulation of cell cycle, chromatin modification, and DNA repair processes with a lack of conservation observed in a relatively ixazomib-resistant cell line, L428. Moreover, the predicted activation and inhibition status of tumor suppressors and oncogenes strongly favored ixazomib inhibition of tumor progression. Most notably, ixazomib down-regulated protein levels of MYC and its target genes. Additionally, chromatin immunoprecipitation showed that histone H3 acetylation affected MYC levels and cell death response to ixazomib. Furthermore, inhibition of MYC with JQ1 resulted in synergistic cell death in L428, which was confirmed utilizing MYC knockout. Collectively, ixazomib down-regulated MYC and downstream substrates in TCL and HL, while resistance appeared mediated through MYC- and CHK1-dependent mechanisms.
Publication Title
Proteasomal Inhibition by Ixazomib Induces CHK1 and MYC-Dependent Cell Death in T-cell and Hodgkin Lymphoma.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 57 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Age-related variations in the methylome associated with gene expression in human monocytes and T cells.
Sample Metadata Fields
Age
View Samples- Homo sapiens
- 57 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
The MESA Epigenomics and Transcriptomics Study has been launched to investigate potential gene expression regulatory methylation sites in humans by examining the association between CpG methylation and gene expression in purified human monocytes from a large study population (community-dwelling participants in the Multi-Ethnic Study of Atherosclerosis (MESA)).
Publication Title
Age-related variations in the methylome associated with gene expression in human monocytes and T cells.
Sample Metadata Fields
Age
View Samples- Homo sapiens
- 12 Downloadable Samples
- IlluminaHiSeq2500
Description
Purpose: The goals of this study were to identify quantitative gene expression differences between wild type, Musashi1 null, Msuashi2 null and Musashi1/Musashi2 null MIAPaCa2 pancreatic cancer cells Overall design: mRNA profiles of MIA PaCa-2 cancer cells were generated by deep sequencing, in triplicate, using Illumina HiSeq2500.
Publication Title
Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Pancreatic intraepithelial neoplasia (PanIN) is a premalignant lesion that can progress to pancreatic ductal adenocarcinoma, a highly lethal malignancy marked by its late stage at clinical presentationand profound drug resistance. Here we developed novel fluorescent reporter mice that show that the stem cell determinant, Musashi (Msi) is a critical element of pancreatic cancer progression.
Publication Title
Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma.
Sample Metadata Fields
Age, Specimen part
View Samples- Homo sapiens
- 26 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
There is an association between transcriptome and the exercise-related phenotype. Peripheral blood cells suffer alterations in the gene expression pattern in response to perturbations caused by exercise. The acute response to endurance activates stress and inflammation, as well as growth and tissue repair responses.
Publication Title
PBMCs express a transcriptome signature predictor of oxygen uptake responsiveness to endurance exercise training in men.
Sample Metadata Fields
Sex, Specimen part, Disease, Disease stage, Treatment, Subject, Time
View Samples