EKLF is a Krppel-like transcription factor identified as a transcriptional activator and chromatin modifier in erythroid cells. EKLF-deficient (Eklf -/-) mice die at day 14.5 of gestation from severe anemia. In this study, we demonstrate that early progenitor cells fail to undergo terminal erythroid differention in Eklf -/- embryos. To discover potential EKLF target genes responsible for the failure of erythropoiesis, transcriptional profiling was performed with RNA from wild type and Eklf -/- early erythroid progenitor cells. These analyses identified significant perturbation of a network of genes involved in cell cycle regulation, with the critical regulator of the cell cycle, E2f2, at a hub. E2f2 mRNA and protein levels were markedly decreased in Eklf -/- early erythroid progenitor cells, which showed a delay in the G1-to-S-phase transition. Chromatin immunoprecipitation analysis demonstrated EKLF occupancy at the proximal E2f2 promoter in vivo. Consistent with the role of EKLF as a chromatin modifier, EKLF binding-sites in the E2f2 promoter were located in a region of EKLF-dependent DNase I sensitivity in early erythroid progenitor cells. We propose a model in which EKLF-dependent activation and modification of the E2f2 locus is required for cell cycle progression preceding terminal erythroid differentiation.
Failure of terminal erythroid differentiation in EKLF-deficient mice is associated with cell cycle perturbation and reduced expression of E2F2.
Age, Specimen part
View SamplesTo investigate downstream targets of PRRX1, we used MDA-MB-231 (MDA231) breast cancer cells which express low level of PRRX1 to generate a stable cell line where human PRRX1 was ectopically overexpressed
A gene regulatory network to control EMT programs in development and disease.
Specimen part
View SamplesPeripheral blood neutrophils were isolated from septic patients and treated in vitro with LPS or HMGB1
HMGB1 and LPS induce distinct patterns of gene expression and activation in neutrophils from patients with sepsis-induced acute lung injury.
No sample metadata fields
View SamplesPurpose: The phosphoinositide 3-kinase (PI3K) pathway is fundamental for cell proliferation and survival and is frequently altered and activated in neoplasia, including carcinomas of the lung. In this study we investigated the potential of targeting the catalytic class IA PI3K isoforms in small cell lung cancer (SCLC), which is the most aggressive of all lung cancer types. Experimental Design: The expression of PI3K isoforms in patient specimens was analyzed. The effects on SCLC cell survival and downstream signaling were determined following PI3K isoform inhibition by selective inhibitors or down-regulation by small interfering RNA. Results: Over-expression of the PI3K isoforms p110 and p110 was shown by immunohistochemistry in primary SCLC tissue samples. Targeting the PI3K p110 with RNA interference (RNAi) or selective pharmacological inhibitors resulted in strongly affected cell proliferation of SCLC cells in vitro and in vivo, while targeting p110 was less effective. Inhibition of p110 also resulted in increased apoptosis and autophagy, which was accompanied by decreased phosphorylation of Akt and components of the mammalian target of rapamycin (mTOR) pathway, such as the ribosomal S6 protein, and the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). A DNA microarray analysis revealed that p110 inhibition profoundly affected the balance of pro- and anti-apoptotic Bcl-2 family proteins. Finally, p110 inhibition led to impaired SCLC tumor formation and vascularization in vivo. Conclusion: Together our data demonstrate the key involvement of the PI3K isoform p110 in multiple tumor-promoting processes in SCLC.
Targeting the phosphoinositide 3-kinase p110-α isoform impairs cell proliferation, survival, and tumor growth in small cell lung cancer.
Cell line, Treatment
View SamplesSensitive versus Resistant patient-derived colorectal cancer tumor xenografts with PIK3CA mutant against saracatinib (AZD0530)
Common PIK3CA mutants and a novel 3' UTR mutation are associated with increased sensitivity to saracatinib.
Specimen part
View SamplesTo understand which genes acts downstream AtHB1 affecting hypocotyl growth in Arabidopsis thaliana, we performed transcriptional profiles of 4-day-old seedlings grown in a short-day regime comparing wild-type with athb1-1 mutant plants. These results show that some of the AtHB1-regulated genes modulate cell elongation, particularly cell wall composition and elongation, or encode proteins that serve as a source of carbon, nitrogen, and sulfur for early seedling growth. Overall design: RNA-Seq data for 4-day-old wild-type (Col-0) and athb1-1 mutant seedlings grown under short-day conditions. Biological triplicates were performed for each genotype analyzed.
Arabidopsis thaliana HomeoBox 1 (AtHB1), a Homedomain-Leucine Zipper I (HD-Zip I) transcription factor, is regulated by PHYTOCHROME-INTERACTING FACTOR 1 to promote hypocotyl elongation.
Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Pluripotent stem cells reveal erythroid-specific activities of the GATA1 N-terminus.
Specimen part, Cell line, Time
View SamplesWe generated human induced pluripotent stem cells (iPSCs) from trisomy 21 (T21) and euploid patient tissues with and without GATA1 mutations causing exclusive expression of truncated GATA1, termed GATA1short (GATA1s). Transcriptome analysis comparing expression levels of genes in GATA1s vs. wtGATA1-expressing progenitors demonstrated that GATA1s impairs erythropoiesis and enhances megakaryopoiesis and myelopoiesis in both T21 and euploid contexts in the iPSC-model system.
Pluripotent stem cells reveal erythroid-specific activities of the GATA1 N-terminus.
Specimen part
View SamplesWe transduced mouse Gata1- megakaryocyte-erythroid progenitors with MIGRI-GFP vector expressing GATA1fl or GATA1s cDNAs. GFP-positive cells expressing one of the two isoforms of GATA1 were isolated by FACS 42 hours following transduction and used for microarray transcriptome analysis. At this time point, there was no apparent difference in the cell surface phenotypes between GATA1fl and GATA1s-expressing cells. Transcriptome data for G1ME/GATA1fl at 42h were deposited previously under GSE14980 (GSM374049, GSM374050, GSM374051), whereas G1ME/GATA1s at 42h are deposited here.
Pluripotent stem cells reveal erythroid-specific activities of the GATA1 N-terminus.
Specimen part
View SamplesMedulloblastoma (MB) is the most common malignant brain tumor in children, among whom overexpression or amplification of MYC oncogenes has been associated with poor clinical outcome. Although the MYC functions during normal development and oncogenesis in various systems have been extensively investigated, the transcriptional targets mediating MYC effects in MB are still elusive. Their identification and roles during MB onset and progression are important and will ultimately suggest novel potential therapeutic targets. cDNA microarray analysis was used to compare the effects of overexpressing and silencing MYC on the transcriptome of a MB-derived cell line. We identified 209 genes with potential relevance to MYC-dependent cellular responses in MB. Among the MYC-responsive genes, we found members of the bone morphogenetic protein (BMP) signaling pathway, which plays a crucial role during the development of the cerebellum. In particular, the cytokine gene BMP7 was identified as a direct target of MYC in MB cells. Similar to the effect induced by BMP7 silencing by siRNA, the use of a small-molecule inhibitor of the BMP/SMAD signaling pathway reduced cell viability in a panel of MB cells. Altogether, our findings indicate that high MYC levels drive BMP7 expression in MB to induce pro-survival and pro-proliferative cellular pathways. This observation suggests that targeting the BMP/SMAD pathway may be a new therapeutic concept for the treatment of childhood MB.
Bone morphogenetic protein-7 is a MYC target with prosurvival functions in childhood medulloblastoma.
Specimen part, Cell line
View Samples