This SuperSeries is composed of the SubSeries listed below.
Identification of the CIMP-like subtype and aberrant methylation of members of the chromosomal segregation and spindle assembly pathways in esophageal adenocarcinoma.
Specimen part
View Samplesgenome-wide methylation profile of 250 samples including 125 EAC, 19 Barretts, 64 normal adjacent squamous and 21 normal stomach. Transcriptome data was performed for 70 samples with methylation profile (48 EAC, 4 Barretts and 18 normal adjacent squamous). This is the first study to use methylome, transcriptome and ENCODE data to characterize the regulatory role of methylation in EAC.
Identification of the CIMP-like subtype and aberrant methylation of members of the chromosomal segregation and spindle assembly pathways in esophageal adenocarcinoma.
Specimen part
View SamplesObjectives: Idiopathic pulmonary fibrosis (IPF) is a complex disease in which a multitude of proteins and networks are disrupted. Interrogation of genome-wide transcription through RNA sequencing (RNA-Seq) enables the determination of genes whose differential expression is most significant in IPF, as well as the detection of alternative splicing events which are not easily observed with traditional microarray experiments. Methods: Messenger RNA extracted from 8 IPF lung samples and 7 healthy controls was sequenced on an Illumina HiSeq. Analysis of differential expression and exon usage was performed using Bioconductor packages. The gene periostin was selected for validation of alternative splicing by quantitative PCR, and pathway analysis was performed to determine enrichment for differentially expressed and spliced genes. Results: There were 873 genes differentially expressed in IPF (FDR 5%), and 440 unique genes had significant differential splicing events (FDR 5%). In particular, cassette exon 21 of the gene periostin was significantly more likely to be spliced out in IPF samples (adj pval = 2.06e-09), and this result was confirmed by qPCR (Wilcoxon pval = 3.11e-4). We also found that genes close to SNPs in the discovery set of a recent IPF GWAS were enriched for genes differentially expressed in our data, including genes like mucin5B and desmoplakin which have been previously associated with IPF. Conclusions: There is significant differential splicing and expression in IPF lung samples as compared with healthy controls. We found a strong signal of differential cassette exon usage in periostin, an extracellular matrix protein whose increased gene-level expression has been associated with IPF and its clinical progression, but for which differential splicing has not been studied in the context of IPF. Our results suggest that alternative splicing of periostin and other genes may be involved in the pathogenesis of IPF. Overall design: mRNA sequencing of 8 IPF and 7 control lung tissue samples.
Transcriptome analysis reveals differential splicing events in IPF lung tissue.
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View SamplesDifferentiation of naive CD4+ T cells into T-helper (Th) effector subsets is critical for protection against pathogens. Together, E-protein transcription factors and the inhibitor-of-DNA binding (Id) proteins are important arbiters of T cell development, but their role in the differentiation of Th1 and Tfh cells is not well understood. Th1 cells show robust Id2 expression compared to Tfh cells, and RNAi depletion of Id2 increased Tfh cell frequencies and germinal center responses, while impairing Th1 cell accumulation during viral infection. Further, Th1 cell differentiation was blocked by genetic ablation of Id2, leading to E-protein dependent accumulation of effector cells with 78% of Th1-associated genes showing diminished expression and a concurrent enrichment of the Tfh gene-expression program. The Tfh-defining transcriptional repressor Bcl6 bound to the Id2 locus inhibiting expression, providing a mechanism by which bimodal expression of Id2 in Tfh and Th1 cells can be established. Thus, Id2 is critical in enforcing the reciprocal development of Th1 and Tfh cell fates.
Id2 reinforces TH1 differentiation and inhibits E2A to repress TFH differentiation.
Age, Specimen part
View SamplesGlucose is the most important metabolic substrate of the retina and maintenance of nor-moglycemia is an essential challenge for diabetic patients. Glycemic excursions could lead to cardiovascular disease, nephropathy, neuropathy and retinopathy. We recently showed that hy-poglycemia induced retinal cell death in mouse via caspase 3 activation and glutathione (GSH) decrease. Ex vivo experiments in 661W photoreceptor cells confirmed the low-glucose induction of death via superoxide production and activation of caspase 3, which was concomitant with a decrease of GSH content. We evaluate herein retinal gene expression 4 h and 48 h after insulin-induced hypoglycemia. Microarray analysis demonstrated clusters of genes whose expression is modified by hypoglycemia and we discuss the potential implication of those genes in retinal cell death. In addition, we highlight, by gene set enrichment analysis, three important pathways, including KEGG lysosomes, KEGG GSH metabolism and REACTOME apoptosis pathways. We tested the effect of recurrent hypoglycemia (three successive 5h periods of hypoglycemia separated by 48 h recovery) on retinal cell death. Interestingly, exposure to multiple hypoglycemic events prevents retinal cell death and GSH decrease, or adapts the retina to external stress by restoring GSH level comparable to control situation. We hypothesize that scavenger GSH is a key compound in this apoptotic process, and maintaining normal GSH level, as well as a strict glycemic control, may represent a therapeutic challenge in order to avoid side effects of diabetes, especially diabetic retinopathy.
Biological Characterization of Gene Response to Insulin-Induced Hypoglycemia in Mouse Retina.
Sex, Age, Specimen part
View SamplesActivating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements (KMT2A-R). These mutations are often subclonal and their biological impact remains unclear. Using a retroviral acute myeloid mouse leukemia model, we demonstrate that FLT3ITD, FLT3N676K, and NRAS G12D accelerate KMT2A-MLLT3 leukemia onset. Subclonal FLT3N676K mutations also accelerate disease, possibly by providing stimulatory factors such as Mif. Acquired de novo mutations in Braf, Cbl, Kras, and Ptpn11 were identified in KMT2A-MLLT3 leukemia cells and favored clonal expansion. During clonal evolution, serial genetic changes at the KrasG12D locus was observed, consistent with a strong selective advantage of additional KrasG12D. KMT2A-MLLT3 leukemias with signaling mutations enforced Myc- and Myb transcriptional modules. Our results provide new insight into the biology of KMT2A-R leukemia with subclonal signaling mutations and highlights the importance of activated signaling as a contributing driver in this disease. Overall design: mRNA sequencing of KMT2A-MLLT3 leukemias with or without activating mutations generated using Illumina NextSeq 500.
De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia.
Specimen part, Cell line, Subject
View SamplesMany neural progenitor cells present in the fetus, but also in adult brain, which play a major role for the reproduction for healingin regeneration of neuronal cells, when differentiated cells are damaged. However, effects of radiation effect on undifferentiated neural progenitor cells remained unclear. The radiation doses of medical exposure, pollution by nuclear power plant accidents, and other exposure of workers; medical workers, airline crews, and astronaut have been focused. In this study, we report the effects of low- to middle- dose doses of radiation on cultured human neural progenitor cells (hNPC) differentiated derived from embryonic stem (ES) cells, which are partially compared with those of human umbilical vein endothelial cell (HUVEC).
Effects of Chronic Low-Dose Radiation on Human Neural Progenitor Cells.
Specimen part, Cell line
View SamplesBulk RNA sequencing data from neural progenitor cells under conditions of low or high growth factor and Notch pathway activation Overall design: Cells were treated with high (20 ng/ml EGF and FGF) or low (0.5 ng/ml EGF) recombinant growth factors, with or without Notch pathway inhibitor (DAPT, 10 uM) for 12h.
<i>Cis-</i>activation in the Notch signaling pathway.
Specimen part, Subject
View SamplesThe complete transcriptomes of kidney cortex from 3 ?-HIF2aM3 18 month old TG+ male mice and 3 age matched wild type (WT) C57BL/6 male mice were sequenced on an Illumina HiSeq2000 Sequencer. Overall design: Examination of complete transcriptome of kidney cortex between ?-HIF2aM3 TG+ male mice and wild type C57BL/6 male mice
Activation of HIF2α in kidney proximal tubule cells causes abnormal glycogen deposition but not tumorigenesis.
Sex, Specimen part, Cell line, Subject
View SamplesAlterations in the composition of the gut microbiome have an emerging role in brain function and behaviour. We have porposed that short chain fatty acids (SCFA) including propionate and butyrate which are present in the diet and are fermantation products of many gastrointestinal bacteria are contributing environmental factors in autism spectrum disorders (ASD). Here we used the microarray technology to compare global changes in gene expression profiles following exposure of PC12 cells to structurally related SCFA propionate and butyrate each in two different concentrations. Large number of affected genes, common for both SCFA were identified, including genetic networks and GO processes implicated in ASD.
Enteric bacterial metabolites propionic and butyric acid modulate gene expression, including CREB-dependent catecholaminergic neurotransmission, in PC12 cells--possible relevance to autism spectrum disorders.
Specimen part
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