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GSE32697
Mus musculus
28 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Thrombospondin 1 (TSP-1) is an anti-angiogenic matricellular protein with regulatory functions in inflammation and cancer. The type 1 repeats (TSR) domains of TSP-1 have been shown to interact with a wide range of proteins that result in the anti-angiogenic and anti-tumor properties of TSP-1. To evaluate potential therapeutic effects of TSRs in inflammatory bowel disease, we conducted clinical, histological and gene microarray analyses on a mouse model of induced colitis.
Publication Title
Thrombospondin-1 type 1 repeats in a model of inflammatory bowel disease: transcript profile and therapeutic effects.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 34 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302), Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
We previously observed that formation of aorta and innominate artery atherosclerotic lesions in the intima of hyperlipidemic apoE-deficient mice but not wild-type mice was accompanied by a marked age-dependent adventitial T cell infiltration. As the mice aged, adventitial T cells formed T/T cell-, T/B cell-, and T/B/dendritic cell aggregates adjacent to atherosclerotic lesions. Some of the adventitial infiltrates formed large clusters of various immune cells including T cells, B cells (centrocytes, follicular mantle cells), dendritic cells, follicular dendritic cells, and plasma cells with preferential formation in the suprarenal portion of the abdominal aorta. These data demonstrated that the immune lineage cell composition of atherosclerotic lesions and adventitia were distinct: The macrophage-foam cell-, T cell-, and SMC-dominated cell composition of atherosclerosis lesions versus the presence of immune cells capable of carrying out antigen-dependent T cell-driven humoral immune responses in the adventitia also indicated that immune reactions carried out in lesions or the adventitia are fundamentaly different. To distinguish between immunity-regulating genes in atherosclerosis lesions versus the adventitia, a combination of microarray profiling and laser capture microdissection was used. Stringent filters revealed 1163 differentially up-regulated probesets in apoE-/- mouse aortae at 78 weeks (w) versus 6 w. A fuzzy c-means cluster algorythm identified 2 clusters that significantly differed in their slope angles between time points: An apparent atherosclerosis cluster consisted of 771 probesets and an apparent adventitia cluster consisted of 392 probesets. Up-regulated genes at 32 w mirrored the influx of monocyte/macrophages into intima lesions whereas genes up-regulated between 32-78 w mirrored adventitial inflammation. To segregate both clusters into separate gene ontology (GO) molecular function groups, we determined statistically significant up-regulation (unpaired Student t-test; p < 0.05) between 6-32 w for the atherosclerosis cluster and between 32-78 w for the adventitia cluster. Among others, GO molecular function terms cytokine activity, cytokine binding, and immunoglobulin binding in the atherosclerosis cluster and cytokine activity, chemokine receptor activity, and antigen binding in the ATLO cluster suggested candidate genes in relation to inflammation triggered by macrophages or adventitia infiltration, respectively. Among other prototype atherosclerosis genes such as Itgax (complement receptor 4), Cd68, Lysz (lysozyme), Vcam1, and Icam1, the atherosclerosis cluster showed markedly overrepresented prototype macrophage/foam cell genes regulating inflammation in cytokine activity (GO: 0005125): Spp1 (osteopontin) and Il6; in cytokine binding (GO: 0019955) Cd74, Il10rb, Ccr2, and Ccr5; and in immunoglobulin binding (GO: 00119865) the proinflammatory galactose-binding lectin Lgals3, as well as genes in scavenger receptor activity and lipid transporter activity. By contrast, the adventitia cluster showed overrepresented genes regulating B cell recruitment, B cell maturation, germinal center formation, and autoimmunity in cytokine activity including Cxcl13, Ccl21, and Ltb, in CXC chemokine receptor activity the secondary lymphoid organ counterreceptor of CXCL13 Blr1 (also known as Cxcr5), Cxcr3, and Cxcr6; and in antigen binding several histocompatibility-2 loci and various markedly expressed immunoglobulin genes. As embryonic lymph node development and tertiary lymphoid organ neogenesis share common features signal intensities of genes specifying the GO molecular function term lymph node development (GO: 0048535) were examined in arrays prepared from wild-type and apoE-/- aortae. These results showed that Id2, Nfkb1, and Ltbr were constitutively expressed at significant levels in aortae of both mouse genotypes whereas other genes including Lta, Ltb, Glycam1, and the two lymphorganogenic genes Cxcl13 and Ccl21 were induced at 78 w in apoE-deficient aortae only. Thus, genes expressed by macrophage-foam cells and genes regulating ATLO neogenesis, embryonic lymph node development, or B cell maturation were constitutively expressed in the arterial wall in both genotypes or emerged in a stepwise fashion at 32 w and 78 w. To verify microarray signal intensity data, separate aortae extracts were examined by quantitative RT-PCR (QRT-PCR) analyses of wild-type and apoE-deficient mice at 32 and 78 w. These data showed that array signal values accurately reflected gene transcripts. Cell lineage analyses of the adventitial infiltrate and kinetic aorta microarray- and QRT-PCR analyses thus provided circumstantial evidence that immune responses in atherosclerosis intima lesions and the adventitia were distinct. To examine this possibility further, we selected areas of the abdominal aorta burdened with advanced lesions and separated lesions and corresponding adventitial infiltrates of 78 w old apoE-deficient mice by laser dissection microscopy. In addition, adventitiae of aorta segments that were not associated with adjacent lesions and adventitiae of wild-type mice were prepared. Consistent with the lack of a major adventitial leukocyte infiltration, wild-type adventitiae showed gene expression levels that were similar to lesion-free adventitiae of apoE-deficient mice indicating that atherosclerotic lesions directly affected adventitial inflammation in a segmental fashion. Stringent filter criteria identified genes that were differentially expressed in adventitiae and atherosclerotic lesions. Statistical analyses of overrepresented genes in GO molecular function or biological process groups were particularly instructive in cytokine activity, cytokine binding, antigen processing and presentation as well as in lymph node development. Thus, adventitiae in aorta segments with associated atherosclerotic lesions in cytokine activity showed overrepresentation of genes known to be associated with tertiary lymphoid organ formation including Cxcl13, Ccl21, and Ltb, whereas atherosclerotic lesions showed overrepresentation of prototype atherosclerosis-associated genes Ssp1 (osteopontin), Bmp4 (bone morphogenic protein 4), and Cxc3cl1 (fractalkine); in cytokine binding adventitiae showed overrepresentation of receptors implicated in B cell immunity and autoimmunity including Brl1 (counterreceptor for CXCL13), Ccr7, Tnfrsf4, and Cxcr3 whereas lesions showed overrepresentation of inflammatory mediator receptors including Tnfrs1b, Tgfbr1, and Il7r; moreover, in antigen processing and presentation, adventitiae showed overrepresentation of several histocompatibility loci; additional adventitial gene expression overrepresentations were observed in lymph node development (Fas, SpiB, Ltb, Flt3) whereas lesions showed expression of prototype macrophage genes including Tlr4, Tgfb1, and Tgfb2. These data provide comprehensive topographical transcriptome information in adventitial tissue adjacent to atherosclerotic lesions versus lesions and are expected to form the basis for future cell lineage expression analyses using single cell detection methodology including ISH.
Publication Title
Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Myeloproliferative neoplasms are frequently associated with aberrant constitutive tyrosine kinase (TK) activity resulting from point mutations or chimaeric fusion genes, such as BCR ABL1 or JAK2 V617F. We report here for the first time in hematological malignancies, two novel fusion genes involving the TK RET, BCR-RET and FGFR1OP-RET, in chronic myelo monocytic leukemia (CMML) cases. The two RET fusion genes lead to the aberrant activation of RET, are able to transform hematopoietic cells and skew the hematopoietic differentiation program towards the monocytic/macrophage lineage. We also report that the BCR-RET fusion protein is insensitive to Imatinib but sensitive to Sorafenib in vivo. CMML is an hematopoietic malignancy associated with the frequent activation of the RAS pathway. The RET fusion genes seems to constitutively mimic the same signaling pathway than RAS mutations. Overall, the RET fusion genes behaviors in the monocytic lineage underlie the role of the normal RET TK activity during the physiological monocytic differentiation.
Publication Title
RET fusion genes are associated with chronic myelomonocytic leukemia and enhance monocytic differentiation.
Sample Metadata Fields
Cell line
View Samples- Mus musculus
- 12 Downloadable Samples
Illumina HiSeq 2000
Description
ING1b and GADD45a are nuclear proteins involved in the regulation of cell growth, apoptosis and DNA repair. We previously found that ING1b is required to target GADD45a-mediated active DNA-demethylation via TET1 to specific loci. In order to study the impact of ING1-GADD45a on gene expression, we compared the expression profile of wildtype mouse embryonic fibroblasts (MEFs) with Ing1- and Gadd45a- single- or double-knockout (DKO) MEFs. Overall design: Gene expression profiling in all 4 genotypes of undifferentiated MEFs in triplicates.
Publication Title
Impaired DNA demethylation of C/EBP sites causes premature aging.
Sample Metadata Fields
Sex, Specimen part, Cell line, Subject
View Samples- Mus musculus
- 19 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Self-renewing tissue-resident macrophages are thought to be exclusively derived from embryonic progenitors. However, whether circulating monocytes can also give rise to such macrophages has not been formally investigated. Here we use a new model of diphtheria toxin-mediated depletion of liver-resident Kupffer cells to generate niche availability and show that circulating monocytes engrafted in the liver, gradually adopt the transcriptional profile of their depleted counterparts and become long-lived self-renewing cells. Underlining the physiological relevance of our findings, circulating monocytes also contribute to the expanding pool of macrophages in the liver shortly after birth, when macrophage niches become available during normal organ growth. Thus, like embryonic precursors, monocytes can and do give rise to self-renewing tissue-resident macrophages if the niche is available to them.
Publication Title
Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 5 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Glucocorticoids (GC) are used as first line therapies for generalized suppression of inflammation (e.g. allergies or autoimmune diseases), but their long-term use is limited by severe side effects. Our previous work has revealed that GC induced a stable anti-inflammatory phenotype in monocytes, the glucocorticoid-stimulated monocytes (GCsM) that we now exploited for targeted GC-mediated therapeutic effects.
Publication Title
Immune suppression via glucocorticoid-stimulated monocytes: a novel mechanism to cope with inflammation.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Sox9 Controls Self-Renewal of Oncogene Targeted Cells and Links Tumor Initiation and Invasion.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Sox9 is a transcription factor expressed in most solid tumors. However, the molecular mechanisms underlying Sox9 function during tumorigenesis remain unclear. Here, using a genetic mouse model of basal cell carcinoma (BCC), the most frequent cancer in human, we show that Sox9 is expressed from the earliest step of tumor formation in a Wnt/-catenin dependent manner. Deletion of Sox9 together with the constitutive activation of Hedgehog (HH) signaling completely prevents BCC formation and leads to a progressive loss of oncogene expressing cells. Transcriptional profiling of oncogene expressing cells with Sox9 deletion, combined with in vivo ChIP-sequencing uncovers a cancer-specific gene network regulated by Sox9 that promotes stemness, extracellular matrix (ECM) deposition and cytoskeleton remodeling while repressing epidermal differentiation. Our study identifies the molecular mechanisms regulated by Sox9 that links tumor initiation and invasion.
Publication Title
Sox9 Controls Self-Renewal of Oncogene Targeted Cells and Links Tumor Initiation and Invasion.
Sample Metadata Fields
Specimen part
View Samples- Rattus norvegicus
- 30 Downloadable Samples
- Illumina HiSeq 2000, Illumina Genome Analyzer IIx
Description
TBI was induced with lateral fluid-percussion injury in adult male rats. Genome-wide RNA-seq of the perilesional cortex, ipsilateral thalamus and dorsal hippocampus was performed at 3 months post-TBI. The data highlighted chronic transcriptional changes, particularly, in the perilesional cortex and thalamus. Genes showing a significantly altered expression both in the cortex and thalamus were submitted to the LINCS web query to identify novel pharmacotherapies to improve post-TBI outcome. Overall design: TBI was induced to 5 rats, 5 sham operated served as a controls.
Publication Title
Analysis of Post-Traumatic Brain Injury Gene Expression Signature Reveals Tubulins, Nfe2l2, Nfkb, Cd44, and S100a4 as Treatment Targets.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
Three human ER+ breast cancer cell lines--MCF-7, T47-D, BT-474--grown with or without estradiol (E2).
Publication Title
GREB 1 is a critical regulator of hormone dependent breast cancer growth.
Sample Metadata Fields
Cell line
View Samples