The ERG gene belongs to the ETS family of transcription factors and has been found involved in atypical chromosomal rearrangements in several cancers. To gain insight into the oncogenic activity of ERG, we compared the gene expression profile of NIH-3T3 cells stably expressing the coding regions of the three main ERG oncogenic fusions: TMPRSS2/ERG (tERG), EWS/ERG and FUS/ERG,. We found that all the three ERG fusions significantly up-regulate PIM-1 expression in the NIH-3T3 cell line. PIM-1 is a serine/threonine kinase frequently over-expressed in cancers of haematological and epithelial origin. We show here that tERG expression induces PIM-1 in the non-malignant prostate cell line RWPE-1, strengthening the relation between tERG and PIM-1 up-regulation in the initial stages of prostate carcinogenesis. Silencing of tERG reversed PIM-1 induction. A significant association between ERG and PIM-1 expression in clinical prostate carcinoma specimens was found, suggesting that such a mechanism may be relevant in vivo. Chromatin Immunoprecipitation experiments showed that tERG directly binds to PIM-1 promoter in the RWPE-1 prostate cell line, suggesting that tERG could be a direct regulator of PIM-1 expression. The up-regulation of PIM-1 induced by tERG over-expression significantly modified CyclinB1 levels and increased the percentage of aneuploid cells in the RWPE-1 cell line after 24hrs of taxane-based treatment. Here we provide the first evidence for an ERG-mediated PIM-1 up-regulation in prostate cells in vitro and in vivo, suggesting a direct effect of ERG transcriptional activity in the alteration of genetic stability.
ERG deregulation induces PIM1 over-expression and aneuploidy in prostate epithelial cells.
Cell line
View SamplesBRAF is the most frequently mutated gene in melanoma. Constitutive activation of mutant BRAFV600E leads to aberrant Ras-independent MAPK signaling and cell transformation. Inhibition of mutant BRAF is a current front-line therapy for such cases, with improved survival compared with chemotherapy. Unfortunately, reactivation of MAPK signaling by several mechanisms has been shown to cause drug resistance and disease recurrence. In this work, we describe the co-occurrence of an in-frame deletion within an amplified BRAFV600E locus, and a missense point mutation of the transcriptional repressor BCORL1, in vemurafenib-resistant A375 melanoma cells. Functional data confirmed that truncated p47BRAFV600E and mutant BCORL1Q1076H both contribute to resistance. Interestingly, either endogenous BCORL1 silencing or ectopic BCORL1Q1076H expression mimicked the effects of a CRISPR/Cas9-edited BCORL1Q1076H locus, suggesting a change-of-function mutation. Transcriptomic data confirmed this hypothesis. Finally, we show that the pan-RAF inhibitor sorafenib is not affected by expression of BRAF deletion variant and effectively synergizes with vemurafenib to block resistant cells, suggesting a possible intervention for this class of mutants. Overall design: Nine total samples: 3 parental plus 3 BCORL1-WT and 3 BCORL1-MUT overexpressing cells
Concomitant BCORL1 and BRAF Mutations in Vemurafenib-Resistant Melanoma Cells.
Cell line, Subject
View SamplesWe investigated the ability of transferrin receptor1 (TfRc) knockout cells to populate different domains of the developing kidney by using a chimeric approach. The TfRc cells developed into all segments of the developing nephron, but there was a relative exclusion from the ureteric bud and a positive bias towards the stromal compartment. Here we conducted a microarray analysis of differential gene expression between TfRc deficient and wild type (wt) cells in chimeric embryonic kidneys derived from embryos created by blastocyst injection of wt blastocysts with TfRc-/- green fluorescent protein-expressing (GFP+) embryonic stem cells.
Scara5 is a ferritin receptor mediating non-transferrin iron delivery.
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View SamplesThis SuperSeries is composed of the SubSeries listed below.
Transcription factor <i>TFCP2L1</i> patterns cells in the mouse kidney collecting ducts.
Specimen part
View SamplesGene expression analysis of mouse kidney after conditional inactivation of transcription factor Tfcp2l1
Transcription factor <i>TFCP2L1</i> patterns cells in the mouse kidney collecting ducts.
Specimen part
View SamplesThe eukaryotic genome is organized in a three-dimensional structure called chromatin, constituted by DNA and associated proteins, the majority of which are histones. Post-translational modifications of histone proteins greatly influence chromatin structure and regulate many DNA-based biological processes. Methylation of lysine 36 of histone 3 (H3K36) is a post-translational modification functionally relevant during early steps of DNA damage repair. Here, we show that the JMJD-5 regulates H3K36 di-methylation and it is required at late stages of double strand break repair mediated by homologous recombination. Loss of jmjd-5 results in hypersensitivity to ionizing radiation and in meiotic defects, and it is associated with aberrant retention of RAD-51 at sites of double strand breaks. Analyses of jmjd-5 genetic interactions with genes required for resolving recombination intermediates (rtel-1) or promoting the resolution of RAD-51 double stranded DNA filaments (rfs-1 and helq-1) suggest that jmjd-5 prevents the formation of stalled postsynaptic recombination intermediates and favors RAD-51 removal. As these phenotypes are all recapitulated by a catalytically inactive jmjd-5 mutant, we propose a novel role for H3K36me2 regulation during late steps of homologous recombination critical to preserve genome integrity. Overall design: RNA sequencing of N2 and jmjd-5(tm3735) at 20C and 25C at generation 1 (G1) and generation 6 (G6)
JMJD-5/KDM8 regulates H3K36me2 and is required for late steps of homologous recombination and genome integrity.
Subject
View SamplesTranscription profiling by array of mouse male retinas to investigate IGF-I-induced chronic gliosis and retinal stress
Insulin-like growth factor I (IGF-I)-induced chronic gliosis and retinal stress lead to neurodegeneration in a mouse model of retinopathy.
Sex, Specimen part
View SamplesThe PLZF transcription factor is essential for osteogenic differentiation of hMSCs, however, its regulation and molecular function during this process is not fully understood. Here we revealed that the ZBTB16 locus encoding PLZF, is repressed by Polycomb (PcG) and H3K27me3 in naïve hMSCs. At the pre-osteoblast stage of differentiation, the locus lost PcG binding and H3K27me3, gained JMJD3 recruitment, and H3K27ac resulting in high expression of PLZF. Subsequently, PLZF was recruited to osteogenic enhancers, influencing H3K27 acetylation and expression of nearby genes important for osteogenic function. Furthermore, we identified a latent enhancer within the ZBTB16/PLZF locus itself that became active, gained PLZF, p300 and Mediator binding and looped to the promoter of the nicotinamide N-methyltransferase (NNMT) gene. The increased expression of NNMT correlated with a decline in SAM levels, which is dependent on PLZF and is required for osteogenic differentiation. Overall design: Effect of PLZF knockdown on osteogenic differentiation of hMSC (RNAseq)
PLZF targets developmental enhancers for activation during osteogenic differentiation of human mesenchymal stem cells.
Specimen part, Subject
View SamplesGuillain-Barré syndrome (GBS) is an immune-mediated peripheral neuropathy that debilitates the voluntary and autonomous response of the patient. In this study the transcriptome of peripheral blood mononuclear cells from a GBS patient and her healthy twin were compared to discover possible correlates of disease progression and recovery. Overall design: Blood samples were collected simultaneously from the Guillain-Barré patient (A) and from her control healthy twin (B) at three different time points during disease progression from hospitalization in the intensive care unit (T1), passing to intermediate care (T2), and at conclusion of locomotion rehabilitation program when the patient was close to abandon the hospital (T3).
Expression of Early Growth Response Gene-2 and Regulated Cytokines Correlates with Recovery from Guillain-Barré Syndrome.
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View SamplesThis SuperSeries is composed of the SubSeries listed below.
Aberrant epigenome in iPSC-derived dopaminergic neurons from Parkinson's disease patients.
Sex, Specimen part, Disease, Disease stage, Subject
View Samples