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GSE90012
Homo sapiens
1 Downloadable Sample
Illumina HumanHT-12 V4.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Depletion of DNMT1 in differentiated human cells highlights key classes of sensitive genes and an interplay with polycomb repression.
Sample Metadata Fields
Sex, Specimen part, Time
View Samples- Homo sapiens
- 1 Downloadable Sample
- Illumina HumanHT-12 V4.0 expression beadchip
Description
DNA methylation plays a vital role in the cell, but loss-of-function mutations of the maintenance methyltransferase DNMT1 in normal human cells are lethal, precluding target identification, and existing hypomorphic lines are tumour cells. We generated instead a hypomorphic series in normal hTERT-immortalised fibroblasts using stably integrated short hairpin RNA. Approx 2/3 of sites showed demethylation as expected, with 1/3 showing hypermethylation, and targets were shared between the three independently-derived lines. Enrichment analysis indicated significant losses at promoters and gene bodies with four gene classes most affected: 1)protocadherins, which are key to neural cell identity; 2)genes involved in fat homeostasis/body mass determination; 3)olfactory receptors and 4) cancer/testis antigen (CTA) genes. Overall effects on transcription were relatively small in these fibroblasts, but CTA genes showed robust derepression. Comparison with siRNA-treated cells indicated that shRNA lines show substantial remethylation over time. Regions showing persistent hypomethylation in the shRNA lines were associated with polycomb repression, and were derepressed on addition of an EZH2 inhibitor. Persistent hypermethylation in shRNA lines was in contrast associated with poised promoters. Our results suggest polycomb marking blocks remethylation and indicate the sensitivity of key neural, adipose, and cancer-associated genes to chronic depletion of maintenance methylation activity.
Publication Title
Depletion of DNMT1 in differentiated human cells highlights key classes of sensitive genes and an interplay with polycomb repression.
Sample Metadata Fields
Sex, Specimen part, Time
View Samples- Homo sapiens
- 14 Downloadable Samples
IlluminaHiSeq2000
Description
Myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML) are characterized by mutations in epigenetic modifiers and aberrant DNA methylation. DNA methyltransferase inhibitors (DMTis) are used to treat these disorders, but response is highly variable with few means to predict which patients will benefit. To develop a molecular means of predicting response at diagnosis, we examined baseline differences in mutations, DNA methylation, and gene expression in 40 CMML patients responsive and resistant to decitabine (DAC). While somatic mutations did not differentiate responders and non-responders, we were able to identify for the first time 158 differentially methylated regions (DMRs) at baseline between responders and non-responders using next-generation sequencing. These DMRs were primarily localized to non-promoter regions and overlapped with distal regulatory enhancers. Using the methylation profiles, we developed an epigenetic classifier that accurately predicted DAC response at the time of diagnosis. We also found 53 differentially expressed genes between responders and non-responders. Genes up-regulated in responders were enriched in the cell cycle, potentially contributing to effective DAC incorporation. Two chemokines overexpressed in non-responders -- CXCL4 and CXCL7 -- were able to block the effect of DAC on normal CD34+ and primary CMML cells in vitro, suggesting their up-regulation contributes to primary DAC resistance. Overall design: mRNA profiling in bone marrow mononuclear cells (BM MNC) from 14 CMML patients (8 decitabine responders vs. 6 non-responders).
Publication Title
Specific molecular signatures predict decitabine response in chronic myelomonocytic leukemia.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 25 Downloadable Samples
- Affymetrix Murine Genome U74A Version 2 Array (mgu74av2)
Description
Pulmonary alveoli are complex architectural units thought to undergo endogenous or pharmacologically induced programs of regeneration and degeneration. To study the molecular mechanism of alveoli loss mice were calorie restricted at different timepoints. Lungs were harvested and processed for RNA extraction.
Publication Title
Calorie-related rapid onset of alveolar loss, regeneration, and changes in mouse lung gene expression.
Sample Metadata Fields
Time
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Murine Genome U74A Version 2 Array (mgu74av2)
Description
It has been shown that dexamethasone (Dex) impairs the normal lung septation that occurs in the early postnatal period. Treatment with retinoic acid (ATRA) abrogates the effects of Dex. To understand the molecular basis for the Dex indiced inhibition of the formation of the alveoli and the ability of ATRA to prevent the inhibition of septation, gene expression was analyzed in 4-day old mice treated with diluent (control), Dex-treated and ATRA+Dex-treated.
Publication Title
DNA microarray analysis of neonatal mouse lung connects regulation of KDR with dexamethasone-induced inhibition of alveolar formation.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 32 Downloadable Samples
- Illumina Genome Analyzer
Description
Uterine double conditional inactivation of Smad2 and Smad3 in mice results in endometrial dysregulation, infertility, and uterine cancer. Smad2/3 cKO mice demonstrate abnormal expression of genes involved in inflammation, cell-cycle checkpoint, migration, steroid biosynthesis, and SMAD1/5-driven genes. We performed RNA-sequencing to identify the gene expression differences between the uterine epithelium of control and Smad2/3 cKO. To control for estrous cycle variations, the uterine epithelium was collected from mice at 0.5 dpc. Global gene expression profiles of Smad2/3 cKO versus control mice was analyzed. Our RNA sequencing analysis was performed at 6 weeks of life and already showed significant differences in migratory (Agr2,Slit2) and inflammatory (Ccl20, Crispld2) markers between Smad2/3 cKO and control mice. Overall design: Two group comparison: uterine epithelium of control and Smad2/3 cKO mice. We generated a conditional knockout of Smad2/3 in the uterus and demonstrated that Smad2/3 plays a critical role in the endometrium, with disruption resulting in pubertal-onset uterine hyperplasia and ultimately fatal uterine cancer.
Publication Title
Uterine double-conditional inactivation of <i>Smad2</i> and <i>Smad3</i> in mice causes endometrial dysregulation, infertility, and uterine cancer.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 39 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Colon cancer invade to depper layer and the expression of major molecules at cancer front change. But the screening of expression changing at cancer front has not be adequtely clarified.
Publication Title
Microarray Analysis of Gene Expression at the Tumor Front of Colon Cancer.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 11 Downloadable Samples
- Illumina HiSeq 2000
Description
Understanding the mechanisms by which cells respond to chemotherapeutics is key to identifying means to improve therapy effiicacy while reducing systemic toxicity of these widely used classes of drugs. While determining the role of NRF2-GSH and ER stress in cells exposed to alkylating compounds such as methyl-methanesulfonate (MMS), we asked if these pathways could also be a general cell damage response relevant to other clinically used chemotherapeutics or if it is an alkylation specific response. With this intent, we performed RNA sequencing of MDA-MB231 breast cancer and U2OS osteosarcoma cells lines treated for 8 hours with a topoisomerase II inhibitor etoposide (20 µM), the antimitotic beta-tubulin-interacting drug paclitaxel (0.2 µM), doxorubicin (1 µM) and compared to MMS (40 µg/mL) treated cells. Doses represent IC50 level after 72 hours exposure. We observed that even though non-alkylating drugs, especially etoposide, caused an increase in the mRNA expression of some NRF2 and ER stress signaling markers, the number and magnitude of upregulation of genes markers in either pathway was more pronounced in alkylation treatments compared to other drugs. This indicates that alterations in NRF2 and ER stress pathways could be more likely associated with differential sensitivity to alkylating chemotherapies. Overall design: MDA-MB231 breast cancer and U2OS osteosarcoma cells lines were treated with the 72 h IC50 dose of etoposide (20 µM), paclitaxel (0.2 µM), doxorubicin (1 µM) or MMS (40 µg/mL) for 8 h, and RNA was extracted and analyzed.
Publication Title
Alkylating Agent-Induced NRF2 Blocks Endoplasmic Reticulum Stress-Mediated Apoptosis via Control of Glutathione Pools and Protein Thiol Homeostasis.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Homo sapiens
- 41 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with preiods of active disease followed by remission.
Publication Title
Transcriptional analysis of the intestinal mucosa of patients with ulcerative colitis in remission reveals lasting epithelial cell alterations.
Sample Metadata Fields
Sex, Age, Treatment
View Samples- Homo sapiens
- 10 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Induction of germline-competent pluripotent stem cells from mouse fibroblasts has been achieved by the ectopic expression of four genes (Oct3/4, Sox2, c-Myc and Klf4). If this method can be applied to humans for the generation of personalized human pluripotent stem cells, it would greatly facilitate the therapeutic application of stem cells by avoiding the problem of immune rejection by the recipient associated with allograft transplants. Here we show that the ectopic expression of the same four genes in human neonatal skin derived cells is sufficient to induce pluripotent stem cells indistinguishable from human embryonic stem cells in morphology, gene expression, DNA methylation, teratoma formation and long term self-renewal ability. Extensive analysis of colonies generated by ectopic expression of these four genes indicates the presence of considerable heterogeneity in the induced colonies. These results provide a new finding to generate human induced pluripotent stem cells from postnatal somatic tissues.
Publication Title
Heterogeneity of pluripotent marker gene expression in colonies generated in human iPS cell induction culture.
Sample Metadata Fields
No sample metadata fields
View Samples