Haploinsufficiency of an RB-E2F1-Condensin II complex causes replication stress and contributes to mesenchymal cancers
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Fred Dick
PROVIDER: E-GEOD-55041 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Genome instability is a characteristic of malignant cells, however, evidence for its contribution to tumorigenesis has been enigmatic. In this study we demonstrate that a complex containing the retinoblastoma protein, E2F1, and Condensin II localizes to major satellite repeats at pericentromeres. In the absence of this complex, this genomic region fails to properly replicate and H2AX phosphorylation at pericentromeric repeats is increased. Our data indicates that these lesions contribute to defective chromosome segregation in the ensuing mitosis. Surprisingly, loss of even one copy of the retinoblastoma gene was sufficient to reduce recruitment of Condensin II to pericentromeres and cause this phenotype. Furthermore, we determined that human RB1 mutation status in cancers of mesenchymal origin correlated with copy number variation, chromosomal gains and losses, as well as chromothriptic rearrangements. Importantly, the magnitude of these chromosomal abnormalities was indistinguishable between RB1+/- and RB1-/- genotypes. Lastly, using gene-targeted mice we determined that mutation of just one copy of the murine Rb1 gene causes sarcomas and lymphomas with increased chromosome copy number variation. Our study connects replication stress with a number of common chromosomal abnormalities in cancer through a dosage sensitive complex present at pericentromeric repeats. CAP-D3 localization was studied in two different genotypes: Rb+/+ and RbΔL/ΔL. As a control, input from the ChIP experiment was also sequenced. The CAP-D3 antibody used was raised against a GST fusion protein containing amino acids 1243-1506 (Coschi et al., 2010).
2014-06-19 | E-GEOD-55040 | biostudies-arrayexpress
Project description:Genome instability is a characteristic of malignant cells, however, evidence for its contribution to tumorigenesis has been enigmatic. In this study we demonstrate that a complex containing the retinoblastoma protein, E2F1, and Condensin II localizes to major satellite repeats at pericentromeres. In the absence of this complex, this genomic region fails to properly replicate and H2AX phosphorylation at pericentromeric repeats is increased. Our data indicates that these lesions contribute to defective chromosome segregation in the ensuing mitosis. Surprisingly, loss of even one copy of the retinoblastoma gene was sufficient to reduce recruitment of Condensin II to pericentromeres and cause this phenotype. Furthermore, we determined that human RB1 mutation status in cancers of mesenchymal origin correlated with copy number variation, chromosomal gains and losses, as well as chromothriptic rearrangements. Importantly, the magnitude of these chromosomal abnormalities was indistinguishable between RB1+/- and RB1-/- genotypes. Lastly, using gene-targeted mice we determined that mutation of just one copy of the murine Rb1 gene causes sarcomas and lymphomas with increased chromosome copy number variation. Our study connects replication stress with a number of common chromosomal abnormalities in cancer through a dosage sensitive complex present at pericentromeric repeats. γH2AX localization was studied in four different genotypes: Rb+/+, RbΔL/+, RbΔL/ΔL, and Rb-/-. As a control, input from the ChIP experiment was also sequenced. The γH2AX antibody used was supplied by Millipore (catalog number 05-636, and lot number 2116620).
2014-06-19 | E-GEOD-51558 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-03-29 | E-GEOD-72736 | biostudies-arrayexpress
Project description:BRAHMA (BRM) is a conserved SWI/SNF-type chromatin remodeling ATPase implicated in many key nuclear events. Histone H3 Lysine 27 (H3K27) demethylases specifically remove the repressive histone mark, trimethylation of H3K27 (H3K27me3). Both proteins are thought to play active roles in regulating gene activities at the chromatin level, but their genome-wide coordination remains to be determined. In Arabidopsis thaliana, RELATIVE OF EARLY FLOWERING 6 (REF6, also known as JMJ12) is the first identified plant H3K27 demethylase. Here, genome-wide analyses revealed that REF6 targets to thousands of genes across the Arabidopsis genome and co-localizes with BRM at more than 1,000 genes, many of which are genes involved in response to various stimuli, especially plant hormones. Loss of REF6 activity results in decreased BRM occupancy at hundreds of BRM-REF6 co-targets, indicating that REF6 is required for the recruitment of BRM to chromatin. Further, REF6 targets to genomic loci that contains the CTCTGTTT motif in vivo through its C2H2 zinger finger domains. Consistently, the two proteins activate the expression of a set of common genes in plant cells. Thus, this work demonstrates a genome-wide coordination between an H3K27me3 demethylase and a chromatin remodelling protein. Examination of global RNA expression in 14-day-old wt, brm-1, ref6-1 and brm-1 ref6-1 seedlings. Three biological replicates for each one.
2016-03-28 | E-GEOD-72260 | biostudies-arrayexpress
Project description:Background: Microorganisms are the major cause of food spoilage during storage, processing and distribution. Pseudomonas fluorescens is a typical spoilage bacterium that contributes to a large extent to the spoilage process of proteinaceous food. RpoS is considered an important global regulator involved in stress survival and virulence in many pathogens. Our previous work revealed that RpoS contributed to the spoilage activities of P. fluorescens by regulating resistance to different stress conditions, extracellular acylated homoserine lactone (AHL) levels, extracellular protease and total volatile basic nitrogen (TVB-N) production. However, RpoS-dependent genes in P. fluorescens remained undefined. Results: RNA-seq transcriptomics analysis combined with quantitative proteomics analysis basing on multiplexed isobaric tandem mass tag (TMT) labeling was performed for the P. fluorescens wild-type strain UK4 and its derivative carrying a rpoS mutation. A total of 375 differentially expressed genes (DEGs) and 212 differentially expressed proteins (DEPs) were identified in these two backgrounds. The DGEs were further verified by qRT-PCR tests, and the genes directly regulated by RpoS were confirmed by 5’-RACE-PCR sequencing. The combining transcriptome and proteome analysis revealed a role of this regulator in several cellular processes, including polysaccharide metabolism, intracellular secretion and extracellular structures, cell well biogenesis, stress responses, ammonia and biogenic amine production, which may contribute to biofilm formation, stress resistance and spoilage activities of P. fluorescens. Moreover, in this work we indeed observed that RpoS contributed to the production of the macrocolony biofilm’s matrix.
2019-11-12 | PXD010845 | Pride
Project description:The Hippo pathway effector YAP1 controls stem cell fate in epithelial tissues, but its role in stem cells of non-epithelial tissues, such as skeletal muscle, is poorly documented. Here we show that sustained YAP1 activity in mouse activated satellite cells in vivo induces rhabdomyosarcoma (RMS) resembling human embryonal RMS (ERMS) with high penetrance and short latency. The transcriptional program of YAP1 in ERMS drives pro-proliferative pathways whilst decreasing MyoD1 and MEF2 pro-differentiation activity to globally maintain the myoblastic phenotype of ERMS. Normalization of YAP1 expression reduced tumor burden and allowed myogenic differentiation of YAP1-driven and RD ERMS xenografts in situ, thereby identifying YAP1 as a potent RMS-causing oncogene and potential target for differentiation therapy. A total of four samples were analyzed. Two ChIP-Seq datasets from RD human cells, containing reads connected to TEAD binding and IgG binding as control/background; two ChIP-Seq datasets from YAP-ERMS mouse cells, containing reads connected to TEAD binding and Input reads as control/background
2014-08-12 | E-GEOD-55186 | biostudies-arrayexpress
Project description:The experiment was aimed toward comparison of the abundance of total, primary and processed transcripts in E. coli strain inactivated for the RNase III relative to the wt strain. Analyzed RNAs were extracted from exponentially grown E. coli cultures at OD650 0.4 in LB medium at 37°C. 5' monophosphate (PSS fraction) and 5'triphosphate (TSS fraction) were tagged with specific primers. The untagged fraction is displayed as the INT fraction.
2020-10-15 | E-MTAB-9507 | biostudies-arrayexpress
Project description:Chimeric mouse embryos were generated as a control experiment to understand the contribution of host vs. injected cells to the developing embryo. Embryos were generated by blastocyst injection of tdTomato-labelled mouse embryonic stem cells into wild type embryos. After blastocyst harvest, cells were flow-sorted before 10X Genomics library preparation and single-cell RNA-sequencing.
2018-12-05 | E-MTAB-7324 | biostudies-arrayexpress
Project description:This dataset contains additional data performed as in the experiment stored at accession E-MTAB-7324. Chimeric mouse embryos were generated as a control experiment to understand the contribution of host vs. injected cells to the developing embryo. Embryos were generated by blastocyst injection of tdTomato-labelled mouse embryonic stem cells into wild type embryos. After blastocyst harvest, cells were flow-sorted before 10X Genomics library preparation and single-cell RNA-sequencing.
2020-08-31 | E-MTAB-8812 | biostudies-arrayexpress
Project description:Chimeric embryos were generated to investigate the effect of Tal1 knockout in mouse embryos by single-cell RNA-sequencing. Tal1 is an essential transcription factor for the formation of the embryonic blood. Embryo chimerism permits the analysis of the effects of Tal1 knockout without the confounding effects of the absence of embryonic blood, which results in global developmental failures. Embryos were generated by blastocyst injection of tdTomato-labelled, Tal1-/- mouse embryonic stem cells into wild type embryos. After blastocyst harvest, cells were flow-sorted before 10X Genomics library preparation and single-cell RNA-sequencing.
2018-12-05 | E-MTAB-6968 | biostudies-arrayexpress