Microarray data allowed detection of genes that are induced by light in the zebrafish pineal gland
The light-induced transcriptome of the zebrafish pineal gland reveals complex regulation of the circadian clockwork by light.
Sex, Specimen part, Treatment, TimeView Samples
The zebrafish pineal gland (epiphysis) is an autonomous clock organ. In addition to being a site of melatonin production, it contains photoreceptor cells and functions as a circadian clock pace maker, making zebrafish a useful model system to study the developmental control of expression of genes associated with melatonin synthesis and photodetection, and the circadian clock. Here we have used DNA microarray technology to study the zebrafish pineal transcriptome. Analysis of gene expression at five different developmental stages (three embryonic and two adult) has revealed a highly dynamic transcriptional profile, revealing many genes that are highly expressed in the pineal gland. Statistical analysis of the data based on Gene Ontology (GO) annotation indicates that many transcription factors and cell cycle genes are highly expressed during embryonic stages, whereas genes dedicated to visual system signal transduction are preferentially expressed in the adult. Furthermore, several genes were identified that exhibit day/night differences in expression. Our data provide a rich source of candidate genes for distinct functions at different stages of pineal gland development.
Transcriptome analysis of the zebrafish pineal gland.
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How spatial chromosome organization influences genome integrity is still poorly understood. Here we show that DNA double-strand breaks (DSBs) mediated by topoisomerase 2 (TOP2) activities, are enriched at chromatin loop anchors with high transcriptional activity. Recurrent DSBs occur at CTCF/cohesin bound sites at the bases of chromatin loops and their frequency positively correlates with transcriptional output and directionality. The physiological relevance of this preferential positioning is indicated by the finding that genes recurrently translocating to drive leukemias, are highly transcribed and are enriched at loop anchors. These genes accumulate DSBs at recurrent hot spots that give rise to chromosomal fusions relying on the activity of both TOP2 isoforms and on transcriptional elongation. We propose that transcription and 3D chromosome folding jointly pose a threat to genomic stability, and are key contributors to the occurrence of genome rearrangements that drive cancer. Overall design: Nuclear RNA profiling in lymphoblastoid TK6 cell line
Spatial Chromosome Folding and Active Transcription Drive DNA Fragility and Formation of Oncogenic MLL Translocations.
Specimen part, Cell line, SubjectView Samples
Gene expression analysis from erythroid progenitors (CD34+/CD71(high)/CD45- mononuclear cells from the bone marrow) of patients with Diamond-Blackfan anemia (due to RPS19 mutations) and control individuals.
Altered translation of GATA1 in Diamond-Blackfan anemia.
Specimen part, DiseaseView Samples
Constitutive activation of EGFR- and NF-kB-dependent pathways is a hallmark of cancer, yet signaling proteins that connect both oncogenic cascades are poorly characterized. Here we define KIAA1199 as a BCL-3- and p65-dependent gene in transformed keratinocytes. KIAA1199 expression is enhanced upon human papillomavirus (HPV) infection and is aberrantly expressed in clinical cases of cervical (pre)neoplastic lesions. Mechanistically, KIAA1199 binds Plexin A2 and protects from Semaphorin 3A-mediated cell death by promoting EGFR stability and signaling. Moreover, KIAA1199 is an EGFR-binding protein and KIAA1199 deficiency impairs EGF-dependent Src, MEK1 and ERK1/2 phosphorylations. Therefore, EGFR stability and signaling to downstream kinases requires KIAA1199. As such, KIAA1199 promotes EGF-mediated epithelial-mesenchymal transition (EMT). Taken together, our data define KIAA1199 as an oncogenic protein induced by HPV infection and constitutive NF-kB activity that transmits pro-survival and invasive signals through EGFR signaling.
NF-κB-induced KIAA1199 promotes survival through EGFR signalling.
Specimen part, Cell line, TreatmentView Samples
Currently there is no method available to predict response to farnesyltransferase inhibitors (FTI). We analyzed gene expression profiles from the bone marrow of patients from a phase 2 study of the FTI tipifarnib, in older adults with previously untreated acute myeloid leukemia (AML). The RASGRP1:APTX gene expression ratio was found to predict response to tipifarnib with the greatest accuracy. This two-gene ratio was validated by quantitative PCR (QPCR) in the newly diagnosed AML cohort. We further demonstrated that this classifier could predict response to tipifarnib in an independent set of 54 samples from relapsed or refractory AML, with a negative predictive value (NPV) and positive predictive value (PPV) of 92% and 28%, respectively (odds ratio of 4.4). The classifier also predicted for improved overall survival (154 vs 56 days, p = 0.0001), which was shown to be independent of other prognostic factors including a previously described gene expression classifier predictive of overall survival. Therefore, these data indicate that a two-gene expression assay may have utility in categorizing a population of AML patients who are more likely to respond to tipifarnib.
A 2-gene classifier for predicting response to the farnesyltransferase inhibitor tipifarnib in acute myeloid leukemia.
Sex, Age, DiseaseView Samples
MgrR is a newly characterized Hfq dependent small RNA RNA. The expression of MgrR is regulated by Two component system, PhoPQ regulon, which senses low Mg2+ in environment. It has been reported that Hfq-binding sRNAs base pair with target RNAs, frequently leading to rapid degradation of target messages or, less frequently, to stabilization, both of which can be assayed by using microarrays. In order to search for the target genes of MgrR, we therefore examined the consequences of MgrR expression on mRNA abundance under two conditions. In condition 1, the chromosomal copy of mgrR was deleted and MgrR was expressed for 15 from an induced plac-mgrR plasmid and compared to cells carrying a vector induced for the same period. In condition 2, the expression of mRNAs was compared in wild-type cells (mgrR+) and the mgrR deletion strain, both grown in LB; because MgrR levels are fairly high under our normal growth conditions, this allowed analysis of both the direct and indirect (long-term) effects of MgrR.
A PhoQ/P-regulated small RNA regulates sensitivity of Escherichia coli to antimicrobial peptides.
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Neural precursor cells (NPCs) in the mammalian neocortex generate various neuronal and glial cell types in a developmental stage-dependent manner. Most neocortical NPCs lose their neurogenic potential after birth. We have previously shown that high mobility group A (HMGA) proteins confer the neurogenic potential on early-stage NPCs during the midgestation period, although the underlying mechanisms are not fully understood. Here we performed microarray analysis and compared expression profiles between control and HMGA2-overexpressed NPCs.
IMP2 regulates differentiation potentials of mouse neocortical neural precursor cells.
Specimen partView Samples
Plant cells contain different O-acetylserine(thiol)lyase (OASTL) enzymes involved in Cys biosynthesis and located in different subcellular compartments. These enzymes are made up of a complex variety of isoforms resulting in different subcellular Cys pools. To unravel the contribution of cytosolic Cys to plant metabolism, we characterized the knockout oas-a1.1 and osa-a1.2 mutants, deficient in the most abundant cytosolic OASTL isoform in Arabidposis thaliana. Total intracellular Cys and glutathione concentrations were reduced, and the glutathione redox state was shifted in favour of its oxidized form. Interestingly, the capability of the mutants to chelate heavy metals did not differ from that of the wild type, but the mutants have an enhanced sensitivity to Cd. With the aim of establishing the metabolic network most influenced by the cytosolic Cys pool, we used the ATH1 GeneChip for evaluation of differentially expressed genes in the oas-a1.1 mutant grown under non-stress conditions. The transcriptomic footprints of mutant plants had predicted functions associated with various physiological responses that are dependent on reactive oxygen species and suggested that the mutant was oxidatively stressed. To further elucidate the specific function(s) of the OAS-A1 isoform in the adaptation response to cadmium we extended the trasncriptome experiment to the wild type and oas-a1.1 mutant plants exposed to Cd. The comparison of transcriptomic profiles showed a higher proportion of genes with altered expression in the mutant than in the wild type, highlighting up-regulated genes identified as of the general oxidative stress response rather than metal-responsive genes.
Knocking out cytosolic cysteine synthesis compromises the antioxidant capacity of the cytosol to maintain discrete concentrations of hydrogen peroxide in Arabidopsis.
Specimen partView Samples