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SRP187881
Saccharomyces cerevisiae
6 Downloadable Samples
NextSeq 500
Description
THO/TREX is a conserved complex with a role in messenger ribonucleoprotein biogenesis that links gene expression and genome instability. Here we show that human THO interacts with MFAP1, a spliceosome-associated factor. Interestingly, MFAP1 depletion impairs cell proliferation and genome integrity, increasing ?H2AX foci and DNA breaks. This phenotype is not dependent either on transcription or RNA-DNA hybrids. Mutations in the yeast orthologous gene SPP381, also confer a similar transcription-independent genome instability supporting a conserved role. MFAP1 depletion has a wide effect on splicing and gene expression in human cells, determined by transcriptome analyses, that affects a number of DNA damage response (DDR) genes, which supports an indirect role of MFAP1 on genome integrity. Our work defines a novel functional interaction between THO and RNA processing and argues that splicing factors may contribute to genome integrity indirectly by regulating the expression of DDR genes rather than by a direct role. Overall design: Analysis of gene expression in the Saccharomyces cerevisiae mutant spp381-ts under 1h of restrictive temperature.
Publication Title
Depletion of the MFAP1/SPP381 Splicing Factor Causes R-Loop-Independent Genome Instability.
Sample Metadata Fields
Cell line, Subject
View Samples- Mus musculus
- 21 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
The Her-2/Neu-positive mouse breast cancer cell line was serially co-cultured with minced brain, bone marrow, and lung tissue in an intravital microscopy chamber mounted on the dorsal skinfold of nude mice, alternating with growth in vitro. Gene expression analysis was performed on the cells grown in culture after sorting and further growth in vitro. Gene expression under these growth conditions differed in time and according to the co-cultivated organ tissue. This study reveals genes that are expressed by cells as they adapt differentially to various foreign tissue microenvironments, and may represent a paradigm to discover gene expression changes that occur immediately upon extravasation when cancer metastasizes.
Publication Title
Effects of different tissue microenvironments on gene expression in breast cancer cells.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 80 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the subseries listed below.
Publication Title
Analysis of independent microarray datasets of renal biopsies identifies a robust transcript signature of acute allograft rejection.
Sample Metadata Fields
Sex, Age, Subject
View Samples- Homo sapiens
- 58 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Specific early diagnosis of renal allograft rejection is gaining importance in the current trend to minimize and individualize immunosuppression. Gene expression analyses could contribute significantly by defining molecular Banff signatures. Several previous studies have applied transcriptomics to distinguish different classes of kidney biopsies. However, the heterogeneity of microarray platforms, clinical samples and data analysis methods complicates the identification of robust signatures for the different types and grades of rejection. To address these issues, a comparative meta-analysis was performed across five different microarray datasets of heterogeneous sample collections from two published clinical datasets and three own datasets including biopsies for clinical indications, protocol biopsies, as well as comparative samples from non-human primates (NHP). This work identified conserved gene expression signatures that can differentiate groups with different histopathological findings in both human and NHP, regardless of the technical platform used. The marker panels comprise genes that clearly support the biological changes known to be involved in allograft rejection. A characteristic dynamic expression change of genes associated with immune and kidney functions was observed across samples with different grades of CAN. In addition, differences between human and NHP rejection were essentially limited to genes reflecting interstitial fibrosis progression. This data set comprises all renal allograft biopsies for clinical indications from patients at Hpital Tenon, Paris (February 2003 until September 2004) and few respective patients from Hpital Bictre, Paris, Hpital Pellegrin, Bordeaux, and Hpital Dupuytren, Limoges, plus control normal kidney samples from Hpital Tenon, Paris, France (first batch).
Publication Title
Analysis of independent microarray datasets of renal biopsies identifies a robust transcript signature of acute allograft rejection.
Sample Metadata Fields
Subject
View Samples- Homo sapiens
- 16 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Specific early diagnosis of renal allograft rejection is gaining importance in the current trend to minimize and individualize immunosuppression. Gene expression analyses could contribute significantly by defining molecular Banff signatures. Several previous studies have applied transcriptomics to distinguish different classes of kidney biopsies. However, the heterogeneity of microarray platforms, clinical samples and data analysis methods complicates the identification of robust signatures for the different types and grades of rejection. To address these issues, a comparative meta-analysis was performed across five different microarray datasets of heterogeneous sample collections from two published clinical datasets and three own datasets including biopsies for clinical indications, protocol biopsies, as well as comparative samples from non-human primates (NHP). This work identified conserved gene expression signatures that can differentiate groups with different histopathological findings in both human and NHP, regardless of the technical platform used. The marker panels comprise genes that clearly support the biological changes known to be involved in allograft rejection. A characteristic dynamic expression change of genes associated with immune and kidney functions was observed across samples with different grades of CAN. In addition, differences between human and NHP rejection were essentially limited to genes reflecting interstitial fibrosis progression. This data set comprises all renal allograft biopsies for clinical indications from patients at Hpital Tenon, Paris (February 2003 until September 2004) and few respective patients from Hpital Bictre, Paris, Hpital Pellegrin, Bordeaux, and Hpital Dupuytren, Limoges, plus control normal kidney samples from Hpital Tenon, Paris, France (first batch).
Publication Title
Analysis of independent microarray datasets of renal biopsies identifies a robust transcript signature of acute allograft rejection.
Sample Metadata Fields
Sex, Age, Subject
View Samples- Homo sapiens
- 14 Downloadable Samples
- Affymetrix Human Transcriptome Array 2.0 (hta20)
Description
We examined if the minimal residual disease (MRD) and the Allelic Ratio (AR) of FLT3 internal tandem duplication (ITD) mutated patients may be prognostic factors. We correlated these parameters both with event free survival (EFS), with incidence of relapse and with gene expression profile (GEP). GEP showed that patients with high-ITD-AR or persistent MRD had different expression profiles. Results indicated that the ITD-AR levels and the MRD after I induction course are associated with transcriptional oncogenic profiles, which highlight differences in epigenetic control that may explain the variability in outcome among FLT3-ITD patients
Publication Title
Characterization of children with FLT3-ITD acute myeloid leukemia: a report from the AIEOP AML-2002 study group.
Sample Metadata Fields
Specimen part, Disease
View Samples- Mus musculus
- 21 Downloadable Samples
- Affymetrix Mouse Expression 430A Array (moe430a)
Description
We previously identified toll-like receptor 4 (Tlr4) as a candidate gene responsible for ozone (O3)-induced pulmonary hyperpermeability and inflammation. The objective of this study was to determine the mechanism through which TLR4 modulates O3-induced pulmonary responses and to utilize transcriptomics to determine TLR4 effector molecules. C3H/HeJ (HeJ; Tlr4 mutant) and C3H/HeOuJ (OuJ; Tlr4 normal), mice were exposed continuously to 0.3 ppm O3 or filtered air for 6, 24, 48 or 72 hr. Affymetrix Mouse430A_MOE gene arrays were used to analyze lung homogenates from HeJ and OuJ mice followed using a bioinformatic analysis. Inflammation was assessed by bronchoalveolar lavage and molecular analysis by ELISA, immunoblotting, and transcription factor activity. TLR4 signals through both the MYD88-dependent and independent pathways in OuJ mice, which involves MAP kinase activation, NF-kappaB, AP-1, and KC. Microarray analyses identifiedTLR4 responsive genes for strain and time in OuJ versus HeJ mice (p<0.05). One significantly upregulated cluster of genes in OuJ were the heat shock proteins (Hspa1b; Hsp70), Hsp90ab1). Furthermore, O3-induced expression of HSP70 protein was increased in OuJ compared to HeJ mice following 24-48 h O3. Moreover, BAL polymorphonuclear leukocytes (PMN) and total protein were significantly reduced in response to O3 in Hspa1a/Hspa1btm1Dix (Hsp70-/-) compared to Hsp70+/+ mice (p<0.05). TLR4 signaling (MYD88-dependent), ERK1/2, AP-1 activity, and KC protein content were also significantly reduced after O3 exposure in Hsp70-/- compared to Hsp70+/+ mice (p<0.05). These studies suggest that HSP70 is involved in the regulation of O3-induced lung inflammation through the TLR4 pathway and provide evidence that HSP70 is an endogenous in vivo TLR4 ligand.
Publication Title
Identification of candidate genes downstream of TLR4 signaling after ozone exposure in mice: a role for heat-shock protein 70.
Sample Metadata Fields
Sex, Specimen part, Treatment
View Samples- Mus musculus
- 29 Downloadable Samples
- Affymetrix Mouse Expression 430A Array (moe430a)
Description
Toll like receptor 4 (TLR4), an innate immunity gene, is involved in responses to several pulmonary agonists including endotoxin (LPS; Poltorak et al.,1998), ozone (O3 ,Kleeberger et. al., 2001), Pseudomonas aeruginosa (Faure et al, 2004), and hyperoxia (Zhang et al, 2005). TLR4 appears to partially mediate the response to LPS- and O3-induced lung injury, however, TLR4 is protective for prevention of injury in Pseudomonas aeruginosa infection and against acute lung injury (hyperoxia). The mechanism behind this protection is unclear. We previously demonstrated that TLR4 was also protective against BHT-induced chronic inflammation and tumor promotion (Bauer et al, 2005). C.C3H-Tlr4Lps-d (BALBLps-d) mice, congenic for a 10 cM region of C3H/HeJ chromosome 4 that contains Tlr4 (Vogel et al, 1994), have a missence mutation that renders TLR4 dysfunctional. The Tlr4 mutation likely abrogates signaling by disrupting a direct point of contact with other signaling molecules (Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004;4(7):499-511.). Bronchoalveolar lavage fluid (BALF) alveolar macrophages, lymphocytes, and total protein content were significantly elevated in BALBLps-d mice compared to BALB/c (BALB; Tlr4 sufficient) mice following chronic BHT (Bauer et al., 2005). BALBLps-d mice also had a significant increase in tumor multiplicity (60%) over that of BALB mice in response to an MCA/BHT tumor promotion protocol. While this was the first model to demonstrate a protective role for TLR4 in chronic lung inflammation and tumorigenesis, the downstream mechanism regulating this protective response remains unknown. Using Affymetrix microarray analysis followed by GeneSpring and Ingenuity pathway analyses, we herein identified known and novel downstream pathways and their interactions that may be involved in the protective mechanism elicited by TLR4. We therefore hypothesize that these pathways and interactions amongst the genes identified during the tumor promotion/chronic inflammation stage are in part influencing the differential strain response observed during tumorigenesis.
Publication Title
Transcriptomic analysis of pathways regulated by toll-like receptor 4 in a murine model of chronic pulmonary inflammation and carcinogenesis.
Sample Metadata Fields
No sample metadata fields
View Samples- Saccharomyces cerevisiae
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
GATA transcription factors are highly conserved among eukaryotes and play roles in transcription of genes implicated in cancer progression and hematopoiesis. However, although their consensus binding sites have been well defined in vitro, the in vivo selectivity for recognition by GATA factors remains poorly characterized. Using ChIP-Seq, we identified the Dal80 GATA factor targets in yeast. Our data reveal Dal80 binding to a large set of promoters, sometimes independently of GATA sites, correlating with nitrogen- and/or Dal80-sensitive gene expression. Strikingly, Dal80 was also detected across the body of promoter-bound genes, correlating with high expression. Mechanistic single-gene experiments showed that Dal80 spreading across gene bodies requires active transcription. Consistently, Dal80 co-immunoprecipitated with the initiating and post-initiation forms of RNA Polymerase II. Our work suggests that GATA factors could play dual, synergistic roles during transcription initiation and post-initiation steps, promoting efficient remodeling of the gene expression program in response to environmental changes. Overall design: Strand-specific total RNA-Seq analysis in wild-type (WT) and dal80-delta (dal80) cells grown in glutamine- and/or proline-containing medium.
Publication Title
Transcription-dependent spreading of the Dal80 yeast GATA factor across the body of highly expressed genes.
Sample Metadata Fields
Subject
View Samples- Homo sapiens
- 6 Downloadable Samples
- Illumina HiSeq 2000
Description
Dysregulated inflammation is implicated in the pathobiology of aging, yet platelet-leukocyte interactions and downstream inflammatory gene synthesis in older adults remains poorly understood. Highly-purified human platelets and monocytes were isolated from healthy younger (age<45, n=37) and older (age60, n=30) adults and incubated together under autologous and non-autologous conditions. Inflammatory gene synthesis by monocytes, basally and in the presence of platelets, was examined. Next-generation RNA-sequencing allowed for unbiased profiling of the platelet transcriptome in aging. Basal IL-8 and MCP-1 synthesis by monocytes alone did not differ between older and younger adults. However, in the presence of autologous platelets, monocytes from older adults synthesized greater IL-8 (415 vs. 92 ng/mL, p<0.0001) and MCP-1 (867150 vs. 21636 ng/mL, p<0.0001) than younger adults. Non-autologous experiments demonstrated that platelets from older adults were sufficient for upregulating inflammatory gene synthesis by monocytes. Using RNA-seq followed by validation via RT-PCR and immunoblot, we discovered that granzyme A (GrmA), a serine protease not previously identified in human platelets, is increased in aging (~9-fold vs. younger adults, p<0.05) and governs increased IL-8 and MCP-1 synthesis through TLR4 and caspase-1. Inhibiting GrmA reduced the excessive IL-8 and MCP-1 synthesis in older adults to levels similar to younger adults. In summary, human aging is associated with changes in the platelet transcriptome and proteome. GrmA is present and bioactive in human platelets, is higher in older adults, and controls inflammatory gene synthesis by monocytes. Alterations in the platelet molecular signature and downstream signaling to monocytes may contribute to dysregulated inflammatory syndromes and adverse outcomes in older adults.
Publication Title
Granzyme A in Human Platelets Regulates the Synthesis of Proinflammatory Cytokines by Monocytes in Aging.
Sample Metadata Fields
Sex, Age, Specimen part, Disease
View Samples