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GSE44460
Homo sapiens
12 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Anti-retroviral therapy (ART) has transformed human immunodeficiency virus (HIV) infection from a fatal illness to a chronic condition by controlling viral replication and restoring immune function. However, chronic T-cell activation can be observed in 20-35% of individuals on ART, resulting in an immune reconstitution inflammatory syndrome (IRIS) [1-3]. IRIS involving the CNS can result in permanent disability and death [4]. Tat is a viral protein produced in HIV-infected cells and released into the extracellular space [5]. We show that the secreted-Tat protein activated uninfected T-cells in an antigen-independent manner without inducing proliferation. Notably, Tat induced the secretion of IL-17 from T-cells and increased the percentage of T-cells with a Th17 phenotype. T-cell activation was independent of the T-cell receptor but dependent on endocytosis of Tat and activation of vascular endothelial growth factor receptor 2 (VEGFR2). Tat induced global changes in histone acetylation and increased HIV infection in non-replicating T-cells. Furthermore, in an individual with CNS IRIS, Tat expressing infiltrates and secretion of IL-17 was detected in the absence of viral replication in the brain. Thus Tat can induce T-cell activation in a paracrine and autocrine manner resulting in propagation of inflammation and increased virulence.
Publication Title
Induction of IL-17 and nonclassical T-cell activation by HIV-Tat protein.
Sample Metadata Fields
Specimen part, Treatment, Time
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We treated intestinal enteroids continuously for 6 days with or without TgfbR1/2 inhibitor (LY2109761) or Tgfb1 ligand
Publication Title
Single cell lineage tracing reveals a role for TgfβR2 in intestinal stem cell dynamics and differentiation.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
We treated intestinal organoids continuously for 5 days with or without TgfbR1/2 inhibitor (LY2109761) or Tgfb1 ligand
Publication Title
Single cell lineage tracing reveals a role for TgfβR2 in intestinal stem cell dynamics and differentiation.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 10 Downloadable Samples
- Affymetrix Mouse Expression 430A Array (moe430a)
Description
Mice lacking p53 and one or two alleles of the cyclin D-dependent kinase inhibitor p18Ink4c are prone to medulloblastoma development. The tumor frequency is increased by exposing postnatal animals to ionizing radiation at a time when their cerebella are developing. In irradiated mice engineered to express a floxed p53 allele and a Nestin-Cre transgene, tumor development can be restricted to the brain. Analysis of these animals indicated that inactivation of one or both Ink4c alleles did not affect the time of medulloblastoma onset but increased tumor invasiveness. All such tumors exhibited complete loss of function of the Patched 1 (Ptc1) gene encoding the receptor for sonic hedgehog, and many exhibited other recurrent genetic alterations, including trisomy of chromosome 6, amplification of N-Myc, modest increases in copy number of the Ccnd1 gene encoding cyclin D1, and other complex chromosomal rearrangements. In contrast, medulloblastomas arising in Ptc1+/- mice lacking one or both Ink4c alleles retained p53 function and exhibited only limited genomic instability. Nonetheless, complete inactivation of the wild type Ptc1 allele was a universal event, and trisomy of chromosome 6 was again frequent. The enforced expression of N-Myc or cyclin D1 in primary cerebellar granule neuron precursors isolated from Ink4c-/-, p53-/- mice enabled the cells to initiate medulloblastomas when injected back into the brains of immunocompromised recipient animals. These engineered tumors exhibited gene expression profiles indistinguishable from those of medulloblastomas that arose spontaneously. These results underscore the functional interplay between a network of specific genes that recurrently contribute to medulloblastoma formation.
Publication Title
Genetic alterations in mouse medulloblastomas and generation of tumors de novo from primary cerebellar granule neuron precursors.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
MicroRNAs (miRNAs) post-transcriptionally regulate the expression of thousands of distinct mRNAs. While some regulatory interactions help to maintain basal cellular functions, others are likely relevant in more specific settings, such as response to stress. Here we describe such a role for the mir-290-295 cluster, the dominant miRNA cluster in mouse embryonic stem cells (mESCs). Examination of a target list generated from bioinformatic prediction, as well as expression data following miRNA loss, revealed strong enrichment for apoptotic regulators, two of which we validated directly: Caspase 2, the most highly conserved mammalian caspase, and Ei24, a p53 transcriptional target. Consistent with these predictions, mESCs lacking miRNAs were more likely to initiate apoptosis following genotoxic exposure to gamma irradiation or doxorubicin. Knockdown of either candidate partially rescued this pro-apoptotic phenotype, as did transfection of members of the mir-290-295 cluster. These findings were recapitulated in a specific mir-290-295 deletion line, confirming that they reflect miRNA functions at physiological levels. In contrast to the basal regulatory roles previously identified, the pro-survival phenotype shown here may be most relevant to stressful gestations, where pro-oxidant metabolic states induce DNA damage. Similarly, this cluster may mediate chemotherapeutic resistance in a neoplastic context, making it a useful clinical target.
Publication Title
A latent pro-survival function for the mir-290-295 cluster in mouse embryonic stem cells.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
NextSeq 500
Description
Bone mineral density (BMD) is a strong predictor of osteoporotic fracture. It is also one of the most heritable disease-associated quantitative traits. As a result, there has been considerable effort focused on dissecting its genetic basis. Here, we performed a genome-wide association study (GWAS) in a panel of inbred strains to identify associations influencing BMD. This analysis identified a significant (P=3.1 x 10-12) BMD locus on Chromosome 3@52.5 Mbp that replicated in two seperate inbred strain panels and overlapped a BMD quantitative trait locus (QTL) previously identified in a F2 intercross. The association mapped to a 300 Kbp region containing four genes; Gm2447, Gm20750, Cog6, and Lhfp. Â Further analysis found that Lipoma HMGIC Fusion Partner (Lhfp) was highly expressed in bone and osteoblasts and its expression was regulated by local expression QTL (eQTL) in multiple tissues. A co-expression network analysis revealed that Lhfp was strongly connected to genes involved in osteoblast differentiation. To directly evaluate its role in bone, Lhfp deficient mice (Lhfp-/-) were created using CRISPR/Cas9. Consistent with genetic and network predictions, bone marrow stromal cells (BMSCs) from Lhfp-/- displayed increased osteogenic differentiation. Lfhp-/- mice also had elevated BMD due to increased cortical bone mass. In conclusion, we used GWAS and systems genetics in mice to identify Lhfp as a regulator of osteoblast activity and bone mass. Overall design: Bones and osteoblast-derived from bone marrow stromal cells were profiles using RNA-seq from CC0016/GeniUnc mice (N=3 biological replicates per sample type)
Publication Title
Mouse genome-wide association and systems genetics identifies Lhfp as a regulator of bone mass.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 47 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Levels of C/EBP are low in myeloid blast crisis (BC) of chronic myelogenous leukemia (CML) and its expression in p210BCR/ABL-expressing hematopoietic cells induces granulocytic differentiation, inhibits proliferation and suppresses leukemogenesis. To assess the mechanisms involved in these effects, C/EBP targets were identified by microarray analyses. Upon C/EBP activation, expression of c-Myb and GATA-2 was repressed in 32D-BCR/ABL, K562 and CML-BC primary cells but only c-Myb levels decreased slightly in CD34+ normal progenitors. The role of these two genes for the biological effects of C/EBP was assessed by perturbing their expression in K562 cells. Expression of c-Myb blocked the proliferation inhibition and differentiation-inducing effects of C/EBP while c-Myb siRNA treatment enhanced C/EBP-mediated proliferation inhibition and induced changes in gene expression indicative of monocytic differentiation. GATA-2 expression suppressed the proliferation inhibitory effect of C/EBP but blocked in part the effect on differentiation; GATA-2 siRNA treatment had no effects on C/EBP induction of differentiation but inhibited proliferation of K562 cells, alone or upon C/EBP activation. In summary, the effects of C/EBP in p210BCR/ABL -expressing cells depend, in part, on transcriptional repression of c-Myb and GATA-2. Since perturbation of c-Myb and GATA-2 expression has non identical consequences for proliferation and differentiation of K562 cells, the effects of C/EBP appear to involve different transcription-regulated targets.
Publication Title
Transcriptional repression of c-Myb and GATA-2 is involved in the biologic effects of C/EBPalpha in p210BCR/ABL-expressing cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus, Homo sapiens
- 48 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Topoisomerases facilitate transcription of long genes linked to autism.
Sample Metadata Fields
Age, Specimen part, Treatment
View Samples- Mus musculus
- 48 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Topoisomerases are necessary for the expression of neurodevelopmental genes, and are mutated in some patients with autism spectrum disorder (ASD). We have studied the effects of inhibitors of Topoisomerase 1 (Top1) and Topoisomerase 2 (Top2) enzymes on mouse cortical neurons. We find that topoisomerases selectively inhibit long genes (>100kb), with little effect on all other gene expression. Using ChIPseq against RNA Polymerase II (Pol2) we show that the Top1 inhibitor topotecan blocks transcriptional elongation of long genes specifically. Many of the genes inhibited by topotecan are candidate ASD genes, leading us to propose that topoisomerase inhibition might contribute to ASD pathology.
Publication Title
Topoisomerases facilitate transcription of long genes linked to autism.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 20 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
In almost every countries the proportion of people over 60 years is growing faster that any other age group. Increased life expectancy is leading to the characterization of specific aspects of aging for the various physiological systems. The study of healthy aging is important to design strategies capable to maximize the health and to prevent chronic diseases in older people. Immunosenscence reflects the age-related changes of the immune system and the reduced capacity of elderly people to cope with new infections. To elucidate changes in gene expression related to systemic aging and immunosenescence in an unbiased manner we performed comparative microarray analysis on whole blood cell from healthy middle-aged versus elderly men, and correlated results with functional measurements of aerobic capacity. Blood cells from elderly subjects showed age-related changes in the expression of several markers of immunosenescence, inflammation and oxidative stress, and showed impairments in metabolic and biosynthetic capacities.
Publication Title
Aging: a portrait from gene expression profile in blood cells.
Sample Metadata Fields
No sample metadata fields
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