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GSE138064
Homo sapiens
140 Downloadable Samples
Affymetrix Human Transcriptome Array 2.0 (hta20)
Description
Background: In multiple sclerosis (MS), immune up-regulation is coupled to subnormal immune response to interferon-β (IFN-β) and low serum IFN-β levels. The relationship between the defect in IFN signalling and acute and long-term effects of IFN-β on gene expression in MS is inadequately understood. Methods: We profiled IFN-β-induced transcriptome shifts, using high-resolution microarrays on 227 mononuclear cell samples from IFN-β-treated MS Complete Responders (CR) stable for five years, and stable and active Partial Responders (PR), stable and active untreated MS, and healthy controls. Findings: IFN-β injection induced short-term changes in 1,200 genes compared to baseline expression after 4-day IFN washout. Pre-injection after washout, and in response to IFN-β injections, PR more frequently had abnormal gene expression than CR. Surprisingly, short-term IFN-β induced little shift in Th1/Th17/Th2 gene expression, but up-regulated immune-inhibitory genes (ILT, IDO1, PD-L1). Expression of 8,800 genes was dysregulated n therapy-naïve compared to IFN-β-treated patients. These long-term changes in protein-coding and long non-coding RNAs affect immunity, synaptic transmission, and CNS cell survival, and correct the disordered therapy-naïve transcriptome to near-normal. In keeping with its impact on clinical course and brain repair in MS, long-term IFN-β treatment reversed the overexpression of proinflammatory and MMP genes, while enhancing genes involved in the oligodendroglia-protective integrated stress response, neuroprotection, and immunoregulation. In the rectified long-term signature, 277 transcripts differed between stable PR and CR patients.
Publication Title
Interferon-β corrects massive gene dysregulation in multiple sclerosis: Short-term and long-term effects on immune regulation and neuroprotection.
Sample Metadata Fields
Age, Specimen part
View Samples- Homo sapiens
- 2 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
Large inter-individual variance has been observed in sensitivity to drugs. To comprehensively decipher the genetic contribution to these variations in drug susceptibility, we present a genome-wide model utilizing human lymphoblastoid cell lines from the International HapMap consortium, of which extensive genotypic information is available, to identify genetic variants that contribute to chemotherapeutic agent-induced cytotoxicity. Our model integrated genotype, gene expression and sensitivity of HapMap cell lines to drugs. Cell lines derived from 30 trios of European descent (CEU) and 30 trios of African descent (YRI) were utilized. Cell growth inhibition at increasing concentrations of etoposide for 72 h was determined using alamarBlue assay. Gene expression on 176 HapMap cell lines (87 CEU and 89 YRI) was determined using the Affymetrix GeneChip Human Exon 1.0ST Array. We evaluated associations between genotype and cytotoxicity, genotype and gene expression and correlated gene expression of the identified candidates with cytotoxicity. The analysis identified 63 genetic variants that contribute to etoposide-induced toxicity through their effect on gene expression. These include genes that may play a role in cancer (AGPAT2, IL1B and WNT5B) and genes not yet known to be associated with sensitivity to etoposide. This unbiased method can be used to elucidate genetic variants contributing to a wide range of cellular phenotypes induced by chemotherapeutic agents.
Publication Title
A genome-wide approach to identify genetic variants that contribute to etoposide-induced cytotoxicity.
Sample Metadata Fields
Sex
View Samples- Homo sapiens
- 125 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [probe set (exon) version (huex10st)
Description
In addition to the differences between populations in transcriptional and translational regulation of genes, alternative pre-mRNA splicing (AS) is also likely to play an important role in regulating gene expression and generating variation in mRNA and protein isoforms. Recently, the genetic contribution to transcript isoform variation has been reported in individuals of recent European descent. We report here results of an investigation of the differences in AS patterns between human populations. AS patterns in 176 HapMap lymphoblastoid cell lines derived from individuals of European and African ancestry were evaluated using the Affymetrix GeneChip Human Exon 1.0 ST Array. A variety of biological processes such as immune response and mRNA metabolic process were found to be enriched among the differentially spliced genes. The differentially spliced genes also include some involved in human diseases that have different prevalence or susceptibility between populations. The genetic contribution to the population differences in transcript isoform variation was then evaluated by a genome-wide association using the HapMap genotypic data on single nucleotide polymorphisms (SNPs). The results suggest that local and distant genetic variants account for a substantial fraction of the observed transcript isoform variation between human populations.
Publication Title
Identification of common genetic variants that account for transcript isoform variation between human populations.
Sample Metadata Fields
Sex
View Samples- Homo sapiens
- 92 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Up-regulation of a HOXA-PBX3 homeobox-gene signature following down-regulation of miR-181 is associated with adverse prognosis in patients with cytogenetically abnormal AML.
Sample Metadata Fields
Sex, Age, Specimen part, Disease, Disease stage
View Samples- Homo sapiens
- 96 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Basal airway epithelial cells (AEC) constitute stem/progenitor cells within the central airways and respond to mucosal injury in an ordered sequence of spreading, migration, proliferation, and dif-ferentiation to needed cell types. However, dynamic gene transcription in the early events after mucosal injury has not been studied in AEC. We examined gene expression using microarrays following mechanical injury (MI) in primary human AEC grown in submersion culture to generate basal cells and in the air-liquid interface to generate differentiated AEC (dAEC) that include goblet and ciliated cells. A select group of ~150 genes was in differential expression (DE) within 2 - 24 hr after MI, and enrichment analysis of these genes showed over-representation of functional categories related to inflammatory cytokines and chemokines. Network-based gene prioritization and network reconstruction using the PINTA heat kernel diffusion algorithm demonstrated highly connected networks that were richer in differentiated AEC compared to basal cells. Similar ex-periments done in basal AEC collected from asthmatic donor lungs demonstrated substantial changes in DE genes and functional categories related to inflammation compared to basal AEC from normal donors. In dAEC, similar but more modest differences were observed. We demon-strate that the AEC transcription signature after MI identifies genes and pathways that are im-portant to the initiation and perpetuation of airway mucosal inflammation. Gene expression oc-curs quickly after injury and is more profound in differentiated AEC, and is altered in AEC from asthmatic airways. Our data suggest that the early response to injury is substantially different in asthmatic airways, particularly in basal airway epithelial cells.
Publication Title
Chemokine expression in the early response to injury in human airway epithelial cells.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 82 Downloadable Samples
- Illumina HumanHT-12 V3.0 expression beadchip
Description
Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) provide a conveniently accessible and renewable resource for functional studies in humans. The ability to accumulate multidimensional data pertaining to the same individual cell lines, from complete genomic sequences to detailed gene regulatory profiles, further enhances the utility of LCLs as a model system. A lingering concern, however, is that the changes associated with EBV transformation of LCLs reduce the usefulness of LCLs as a surrogate model for primary tissues. To evaluate the validity of this concern, we compared global gene expression profiles between CD20+ primary B cells and CD3+ primary T cells sampled from six individuals. Six independent replicates of transformed LCLs were derived from each sample.
Publication Title
The effects of EBV transformation on gene expression levels and methylation profiles.
Sample Metadata Fields
Sex, Specimen part, Subject
View Samples- Homo sapiens
- 92 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
Increased expression levels of miR-181 family members have been shown to be associated with favorable outcome in patients with cytogenetically normal acute myeloid leukemia. Here we show that increased expression of miR-181a and miR-181b is also significantly (P < .05; Cox regression) associated with favorable overall survival in cytogenetically abnormal AML (CA-AML) patients. We further show that up-regulation of a gene signature composed of 4 potential miR-181 targets (including HOXA7, HOXA9, HOXA11, and PBX3), associated with down-regulation of miR-181 family members, is an independent predictor of adverse overall survival on multivariable testing in analysis of 183 CA-AML patients. The independent prognostic impact of this 4-homeobox-gene signature was confirmed in a validation set of 271 CA-AML patients. Furthermore, our in vitro and in vivo studies indicated that ectopic expression of miR-181b significantly promoted apoptosis and inhibited viability/proliferation of leukemic cells and delayed leukemogenesis; such effects could be reversed by forced expression of PBX3. Thus, the up-regulation of the 4 homeobox genes resulting from the down-regulation of miR-181 family members probably contribute to the poor prognosis of patients with nonfavorable CA-AML. Restoring expression of miR-181b and/or targeting the HOXA/PBX3 pathways may provide new strategies to improve survival substantially.
Publication Title
Up-regulation of a HOXA-PBX3 homeobox-gene signature following down-regulation of miR-181 is associated with adverse prognosis in patients with cytogenetically abnormal AML.
Sample Metadata Fields
Sex, Age, Specimen part, Disease, Disease stage
View Samples- Homo sapiens
- 80 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [probe set (exon) version (huex10st)
Description
Intragenic microRNAs (miRNAs), including both intronic and exonic miRNAs, accounting approximately 50% of total mammalian miRNAs. Previous studies showed that intragenic miRNAs are often co-expressed with their host genes, and thus it was believed that intragenic miRNAs and their host genes are derived from the same primary transcripts. However, we provide evidence to show here that the observations from previous studies might be biased due to the small number and the predominance of "broadly conserved" intronic miRNAs they studied.
Publication Title
Young intragenic miRNAs are less coexpressed with host genes than old ones: implications of miRNA-host gene coevolution.
Sample Metadata Fields
Disease, Disease stage, Cell line
View Samples- Homo sapiens
- 26 Downloadable Samples
- Illumina HumanRef-8 v3.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
PPARG binding landscapes in macrophages suggest a genome-wide contribution of PU.1 to divergent PPARG binding in human and mouse.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Homo sapiens
- 26 Downloadable Samples
- Illumina HumanRef-8 v3.0 expression beadchip
Description
Genome-wide comparisons of transcription factor binding sites in different species allow for a direct evaluation of the evolutionary constraints that shape transcription factor binding landscapes. To gain insights into the evolution of the PPARg-dependent transcriptional network we obtained binding data for PPARg, RXR and PU.1 in human macrophages and compared the profiles to matching data from mouse macrophages. We found that PPARg binding was highly divergent and only 5% of the PPARg bound regions were occupied in both species. Despite the low conservation of PPARg binding sites, conserved PPARg target genes contribute more than 30% to the functional target genes identified in human macrophages. In addition conserved target genes are strongly enriched for lipid metabolic functions. We detected the lineage-specification factor PU.1 at the majority of human PPARg binding sites. This confirmed the juxtaposed binding configuration found in mouse macrophages and demonstrated the preservation of tissue-specific adjacent PPARg-Pu.1 binding in the absence of individual binding site conservation. Finally, based on this of PPARg and PU.1 binding between human and mouse we suggest a mechanism by which PU.1 facilitates PPARg binding site turnover in macrophages.
Publication Title
PPARG binding landscapes in macrophages suggest a genome-wide contribution of PU.1 to divergent PPARG binding in human and mouse.
Sample Metadata Fields
Cell line, Treatment
View Samples