Activation of the MLL-ENL-ERtm oncogene initiates aberrant proliferation of myeloid progenitors. Here, we show induction of a fail-safe mechanism mediated by the DNA damage response (DDR) machinery that results in activation of the ATR/ATM-Chk1/Chk2-p53/p21 checkpoint and cellular senescence at early stages of cellular transformation caused by a regulatable MLL-ENL-ERtm in mice. Furthermore, we identified the transcription program underlying this intrinsic anti-cancer barrier, and DDR-induced inflammatory regulators that fine-tune the signaling towards senescence, thereby modulating the fate of MLL-ENL-immortalized cells in a tissue-environment-dependent manner. Our results indicate that DDR is a rate-limiting event for acquisition of stem cell-like properties in MLL-ENL-ERtm-mediated transformation, as experimental inhibition of the barrier accelerated the transition to immature cell states and acute leukemia development.
DNA damage response and inflammatory signaling limit the MLL-ENL-induced leukemogenesis in vivo.
Specimen part, Disease stage
View SamplesExposure to high irradiance results in dramatic changes in nuclear gene expression in plants. However, little is known about the mechanisms by which changes in irradiance are sensed and how the information is transduced to the nucleus to initiate the genetic response. To investigate whether the photoreceptors are involved in the response to high irradiance, we analyzed expression of ELIP1, ELIP2, APX2 and LHCB2.4 in the phyA, phyB, cry1 and cry2 photoreceptor mutants and hy5 and hyh transcription factor mutants. Following exposure to high intensity white light for 3 h (HL, 1000 micro mol quanta m-2 s-1) expression of ELIP1/2 and APX2 was strongly induced and LHCB2.4 expression repressed in wild type. The cry1 and hy5 mutants showed specific mis-regulation of ELIP1/2 and we show that the induction of ELIP1/2 expression is mediated via CRY1 in a blue light intensity-dependent manner. Furthermore, using the Affymetrix Arabidopsis 24K Gene-Chip we showed that 77 of the HL responsive genes are regulated via CRY1, and 26 of those genes were also HY5 dependent. As a consequence of the mis-regulation of these genes the cry1 mutant displayed a high irradiance-sensitive phenotype with significant photoinactivation of PSII, indicated by reduced Fv/Fm. Thus, we describe a novel function of CRY1 in mediating plant responses to high irradiances that is essential to the induction of photoprotective mechanisms. This indicates that high irradiance can be sensed in a chloroplast-independent manner by a cytosolic/nucleic component.
Genome-wide gene expression analysis reveals a critical role for CRYPTOCHROME1 in the response of Arabidopsis to high irradiance.
No sample metadata fields
View SamplesWe report RNAseq data from HCT-15 cells were treated wih control(DMSO), GDC-0973, G007-LK and combined GDC-0973 and G007-LK treatmetn for 24 hours. Overall design: Three biological replicates of cultured HCT-15 cells treated with DMSO (0.02%), G007-LK (1µM), GDC-0973 (1µM) or G007-LK and GDC-0973 for 24 hours before Rna extraction
MEK Inhibition Induces Canonical WNT Signaling through YAP in <i>KRAS</i> Mutated HCT-15 Cells, and a Cancer Preventive FOXO3/FOXM1 Ratio in Combination with TNKS Inhibition.
Specimen part, Treatment, Subject
View SamplesPositioned nucleosomes limit the access of proteins to DNA and implement regulatory features encoded in eukaryotic genomes. Here we generated the first genome-wide nucleosome positioning map for Schizosaccharomyces pombe and annotated transcription start and termination sites genome-wide. Using this resource we found surprising differences compared to the nucleosome organization in the distantly related yeast Saccharomyces cerevisiae [the cerevisiae data has been published by others (PMID: 17873876) and the raw data is deposited at ArrayExpress(E-MEXP-1172)]. DNA sequence guides nucleosome positioning differently, e.g., poly(dA:dT) elements are not enriched in S. pombe nucleosome-depleted regions (NDRs). Regular nucleosomal arrays emanate more asymmetrically, i.e., mainly co-directionally with transcription, from promoter NDRs, but promoters harbouring the histone variant H2A.Z show regular arrays also upstream. Regular nucleosome phasing in S. pombe has a very short repeat length of 154 base pairs, and requires a remodeler, Mit1, conserved in humans but not found in S. cerevisiae. Nucleosome positioning mechanisms are evidently not universal but evolutionarily plastic.
Schizosaccharomyces pombe genome-wide nucleosome mapping reveals positioning mechanisms distinct from those of Saccharomyces cerevisiae.
No sample metadata fields
View SamplesWe extracted RNA from whole cells and RNA from the cytoplasm and performed RNA sequening to compare differences in gene expression level and investigate what is the most appropriate estimate of the amount of mRNA present in a given cell population. The study was based on three human cell lines. Overall design: Analyze of transcriptome in 3 human cell lines (U-2 OS, A-431, U-251MG). Each cell line was prepared with four biological replicates for total RNA and four for cytoplasmic RNA.
Comparison of total and cytoplasmic mRNA reveals global regulation by nuclear retention and miRNAs.
No sample metadata fields
View Samplesused to identify differences between tissues from patients undergoing surgery for BPH with unresolved symptoms compared to incidental BPH from patients with prostate cancer
Surgical intervention for symptomatic benign prostatic hyperplasia is correlated with expression of the AP-1 transcription factor network.
Specimen part
View SamplesSmall cell lung cancer (SCLC) is an aggressive cancer often diagnosed only after it has metastasized to distant sites (Meuwissen and Berns 2005; Cooper and Spiro 2006). Despite the need to better understand this disease, SCLC remains poorly characterized at the molecular and genomic levels (Forgacs et al. 2001; Pleasance et al. 2010). Using a genetically-engineered mouse model of SCLC driven by conditional deletion of Trp53 and Rb1 in the lung (Jonkers et al. 2001; Vooijs et al. 2002; Meuwissen et al. 2003; Sage et al. 2003), we identified several frequent, high-magnitude focal DNA copy number alterations in SCLC. We uncovered amplification of a novel, oncogenic transcription factor, Nuclear Factor I/B (Nfib) in the mouse SCLC model and in human SCLC. Functional studies indicate that NFIB regulates cell viability and proliferation during transformation.
Nuclear factor I/B is an oncogene in small cell lung cancer.
Cell line
View SamplesAnalysis of gene expression in prostatic tissue from BPH patients with and without SRD5A2 gene methylation. The hypothesis is that BPH patients with DNA methylation of the SRD5A2 gene promoter have impaired conversion of testosterone to dihydrotestosterone, and therefore may use an alternative signaling pathway for prostatic tissue growth. Here, we compare gene expression profiles of SRD5A2-methylated vs. unmethylated prostatic tissue to nominate alternative biological pathways relevant in each molecular subtype of BPH.
Androgenic to oestrogenic switch in the human adult prostate gland is regulated by epigenetic silencing of steroid 5α-reductase 2.
Sex, Specimen part
View SamplesmRNA expression profiling of pancreatic cancer, comparing adjacent normal tissue, patient tumour and first generation patient derived xenograft tumours
Establishment and Characterisation by Expression Microarray of Patient-Derived Xenograft Panel of Human Pancreatic Adenocarcinoma Patients.
Specimen part
View SamplesWe explored the transcriptional response to parasitoid attack in Drosophila larvae at nine time points following parasitism, hybridizing five biologic replicates per time point to whole-genome microarrays for both parasitized and control larvae. We found significantly different expression profiles for 159 probe sets (representing genes), and we classified them into 16 clusters based on patterns of co-expression. A series of functional annotations were nonrandomly associated with different clusters, including several involving immunity and related functions. We also identified nonrandom associations of transcription factor binding sites for three main regulators of innate immune responses (GATA/srp-like, NF-kappaB/Rel-like and Stat), as well as a novel putative binding site for an unknown transcription factor. The appearance or absence of candidate genes previously associated with insect immunity in our differentially expressed gene set was surveyed
Genome-wide gene expression in response to parasitoid attack in Drosophila.
Time
View Samples