Coordinated control of senescence by lncRNA UCA1 and a novel CAPERα/TBX3 co-repressor
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: anne moon
PROVIDER: E-GEOD-76572 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Coordination of a complex series of transcriptional, structural and signaling events culminates in cellular senescence, a crucial tumor suppressor mechanism. We have discovered a repressor complex composed of TBX3 and CAPERa which functions upstream of the RB and p53 effector pathways and is required to prevent senescence of primary cells and in mouse embryos. TBX3/ CAPERa directly binds and represses transcription and chromatin structure of genes in multiple senescence pathways and the LncRNA UCA1, which we have identified as a novel tumor suppressor. The TBX3/ CAPERa complex is physically disrupted in oncogene induced senescence, providing a new molecular mechanism for derepression of prosenescence pathways in this system. Our results provide new insight into the oncogenic properties of TBX3, and are the first demonstration of CAPERa and UCA1 function in vivo.
2016-01-07 | GSE76572 | GEO
Project description:We used a mouse strain in which one Tbx3 gene was replaced with the yellow fluorescent protein variant Venus. Luminal cells had either very high Tbx3 promoter activity or not at all. We performed an expression analysis on luminal mammary epithelial cells sorted based on their Venus expression (reporting Tbx3 promoter activity) to investigate the difference between these two cell populations. Mammary epithelial cells from 3 Tbx3-Venus-KI adult virgin female mice (FVB background) were pooled and luminal cells were sorted into a Venus-hi and a Venus-neg sample. There were no repeats for this study.
2014-08-20 | E-GEOD-58327 | biostudies-arrayexpress
Project description:Induced pluripotent stem (iPS) cells can be obtained through the introduction of defined factors into somatic cells. The combination of Oct4, Sox2 and Klf4 (OSK) constitutes the minimal requirement for generating iPS cells from mouse embryonic fibroblasts (MEFs). Through the genomic analyses of ESC genes that have roles in pluripotency and fusion-mediated somatic cell reprogramming, we identified Tbx3 as a transcription factor that significantly improves the quality of iPS cells. Induced-PS cells generated with OSK + Tbx3 (OSKT) are superior in both germ cell contribution to the gonads and germ-line transmission frequency. However, global gene expression profiling could not distinguish between OSK and OSKT iPS cells. Genome-wide ChIP-sequencing analysis of Tbx3 binding sites in ESCs suggests that Tbx3 regulates pluripotency-associated and reprogramming factors, in addition to sharing many common downstream regulatory targets with Oct4, Sox2, Nanog and Smad1. ChIP-seq of Tbx3 binding in mouse ESCs
2009-12-04 | E-GEOD-19219 | biostudies-arrayexpress
Project description:The CCR4-NOT complex, bearing poly(A) deadenylation activity, is a highly conserved regulator that is involved in biological control; however its action mechanisms and physiological targets remain unclear. Using genetic deletion of the CNOT3 subunit of this complex in early B cell progenitors, we show that CNOT3 plays a critical role in pro- to pre-B cell transition. CNOT3 participated in controlling germline transcription, compaction of the immunoglobulin heavy chain (Igh) locus, and Igh rearrangement, and in destabilizing tumor suppressor p53 mRNA. Moreover, by genetic ablation of p53 or introduction of pre-rearranged Igh transgene, the B cell developmental defect in the Cnot3 knockout background could be partly rescued, suggesting that CCR4-NOT complex exerts critical control in B cell differentiation processes by co-utilizing transcriptional and post-transcriptional mechanisms. Pro-B cells mRNA profiles of Mb1(cre/+) and Cnot3(fl/fl)Mb1(cre/+) mice were generated by deep sequencing using Illumina HiSeq 1500
2015-07-23 | E-GEOD-64455 | biostudies-arrayexpress
Project description:About 500 forelimbs were isolated at 10.5 days post coitum, and ChIP-seq was performed using anti-BCL9 (Abcam, ab37305) and anti-TBX3 (Santacruz, sc17871) antibodies. BCL9 is a beta-catenin transcriptional cofactor involved in the transcriptional machinery of Wnt target genes. TBX3 is a transcription factor important in limb development. This experiment identified, in this developmental context, co-occupancy of BCL9 and TBX3 on a genome-wide scale, and at Wnt-related loci, suggesting co-operation between these transcription factors in Wnt-driven limb development (Zimmerli et al. in revision during spring 2020). The following files are available for this experiment: - Raw sequencing data (.fastq) - Genomic enrichment data in bedgraph format (.bdg) which can be used for visualization in a genome browser. - Annotated peak files (.txt) containing high confidence peaks with genomic annotation. NOTE: The raw data relative to the BCL9 ChIP were previously deposited under accession number E-MTAB-7652, and described in Salazar et al. 2019. For simplicity, and to allow easy retrieval, we add the raw data of the entire experiment (including also BCL9) along with the newly generated analyses.
2020-05-08 | E-MTAB-8997 | biostudies-arrayexpress
Project description:Toxoplasma gondii multiplies inside a parasitophorous vacuole in the host cell. Several parasite proteins have been described that hijack host signaling pathways, which mostly originate from the rhoptry organelles. We report here the identification and characterization of GRA16, the first dense granule protein shown to be exported through the parasitophorous vacuole membrane and to reach the host cell nucleus. Transcriptomic analysis revealed that GRA16 positively modulates the expression of host genes involved in cell-cycle progression and the p53 tumor suppressor pathway. We show that GRA16 directly binds two host enzymes, the deubiquitinase HAUSP and the phosphatase PP2A, and that GRA16 alters p53 protein levels in a HAUSP-dependent manner and induces the nuclear translocation of the PP2A holoenzyme. Therefore GRA16 is a novel regulator of the HAUSP/p53 pathway and together with GRA15, emerge as a subfamily of new dense granule proteins exported beyond the tachyzoites-hosting vacuole to subvert the host transcriptome. Mouse bone marrow-derived macrophages (BMDM) or Human foreskin fibroblasts (HFFs) were infected with the following Toxoplasma gondii strains: - RHku80 WT versus RHku80(deltaGRA16) mutant (in BMDM) - Pruku80 WT versus Pruku80(deltaGRA16) mutant (in BMDM) - RHku80 WT versus RHku80(deltaGRA16) mutant (in HFF)
2013-02-06 | E-GEOD-38779 | biostudies-arrayexpress
Project description:This is the model described in: Feedback between p21 and reactive oxygen production is necessary for cell senescence.
Passos JF, Nelson G, Wang C, Richter T, Simillion C, Proctor CJ, Miwa S, Olijslagers S, Hallinan J, Wipat A, Saretzki G, Rudolph KL, Kirkwood TB, von Zglinicki T. ;Mol Sys Biol2010;6:347. Epub 2010 Feb 16. PMID:20160708 doi:10.1038/msb.2010.5;
Abstract:
Cellular senescence--the permanent arrest of cycling in normally proliferating cells such as fibroblasts--contributes both to age-related loss of mammalian tissue homeostasis and acts as a tumour suppressor mechanism. The pathways leading to establishment of senescence are proving to be more complex than was previously envisaged. Combining in-silico interactome analysis and functional target gene inhibition, stochastic modelling and live cell microscopy, we show here that there exists a dynamic feedback loop that is triggered by a DNA damage response (DDR) and, which after a delay of several days, locks the cell into an actively maintained state of 'deep' cellular senescence. The essential feature of the loop is that long-term activation of the checkpoint gene CDKN1A (p21) induces mitochondrial dysfunction and production of reactive oxygen species (ROS) through serial signalling through GADD45-MAPK14(p38MAPK)-GRB2-TGFBR2-TGFbeta. These ROS in turn replenish short-lived DNA damage foci and maintain an ongoing DDR. We show that this loop is both necessary and sufficient for the stability of growth arrest during the establishment of the senescent phenotype.
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2010 The BioModels.net Team.For more information see the terms of use.To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2024-09-02 | BIOMD0000000287 | BioModels
Project description:Purpose: Identify cellular pathways controlled by Tbx3 Methods: RNA sequencing of hypothalamic primary neurons from Tbx3 loxP/loxP mice infected with Ad-Cre or Ad-GFP viruses. Results: Unbiased pathway analysis revealed that Tbx3 deletion in primary neurons significantly affected the expression of genes involved in several pathways responsible for controlling cellular proliferation, differentiation and determination of cellular fate. Conclusions: Tbx3 in primary neurons might be implicated in the development and maintenance of neuronal identity.
2019-01-22 | GSE119883 | GEO
Project description:Cellular senescence is a program of irreversible cell cycle arrest that normal cells undergo in response to progressive shortening of telomeres, changes in telomeric structure, oncogene activation or oxidative stress. The underlying signalling pathways, potentially of major clinicopathological relevance, are unknown. A major stumbling block to studying senescence has been the absence of suitable model systems because of the asynchrony of this process in heterogeneous cell populations. To simplify this process many investigators study oncogene-induced senescence due to expression of activated oncogenes where senescence occurs prematurely without telomere attrition and can be induced acutely in a variety of cell types. We have taken a different approach by making use of the finding that reconstitution of telomerase activity by introduction of the catalytic subunit of human telomerase alone is incapable of immortalising all human somatic cells, but inactivation of the p16-pRB and p53-p21 pathways are required in addition. The ability of SV40 large T antigen to inactivate the p16-pRB and p53-p21 pathways has enabled us to use a thermolabile mutant of LT antigen, in conjunction with hTERT, to develop conditionally immortalised human (HMF3A) fibroblasts that are immortal but undergo an irreversible growth arrest when the thermolabile LT antigen is inactivated leading to activation of pRB and p53. When these cells cease dividing, senescence-associated- b-galactosidase activity is induced and the growth-arrested cells have morphological features and express genes in common with senescent cells. Since these cells growth arrest in a synchronous manner they are an excellent starting point for dissecting the pathways that underlie cellular senescence and act downstream of p16-pRB and p53-p21 pathways. We have combined genome-wide expression profiling with genetic complementation to undertake identification of genes that are differentially expressed when these conditionally immortalised human fibroblasts undergo senescence upon activation of the p16-pRB and p53-p21 tumour suppressor pathways. Genes differentially expressed upon senescence will be identified by comparing arrays from growing versus senescent cells. Changes in gene expression due to the temperature shift will be eliminated by comparing with array data from the non-conditional HMF3S cells grown at 34°C ±0.5°C and 38°C ±0.5°C. To determine if the changes in gene expression upon senescence are specific and reversible, the set of differential genes will then be overlaid with array data from cells in which senescence has been bypassed by inactivation of the p16-pRB and p53-p21 tumour suppressor pathways
2011-01-21 | E-GEOD-24810 | biostudies-arrayexpress
Project description:Two major genetic pathways leading to colorectal carcinoma can well be distinguished; the ‘suppressor pathway’, which is characterized by inactivation of tumor-suppressor genes and the ‘mutator pathway’, which is characterized by microsatellite instability. The purpose of this study is to explore a third putative pathway; microsatellite and chromosome stable colorectal cancer where an alternative cancer-causative mechanism might play a role.
| 2021019 | ecrin-mdr-crc