Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Tissue-infiltrating macrophages mediate an exosome-based metabolic reprogramming upon DNA damage

ABSTRACT: DNA damage and metabolic disorders are intimately linked with premature disease onset but the underlying mechanisms remain poorly understood. Here, we show that persistent DNA damage accumulation in tissue-infiltrating macrophages carrying an ERCC1-XPF DNA repair defect (Er1F/-) riggers Golgi dispersal, dilation of endoplasmic reticulum, autophagy and exosome biogenesis leading to the secretion of extracellular vesicles (EVs) in vivo and ex vivo. Macrophage-derived EVs accumulate in Er1F/- animal sera and are secreted in macrophage media after DNA damage. The Er1F/- EV cargo is taken up by recipient cells leading to an increase in insulin-independent glucose transporter levels, enhanced cellular glucose uptake, higher cellular oxygen consumption rate and greater tolerance to glucose challenge in mice. We find that high glucose in EV-targeted cells triggers pro-inflammatory stimuli via mTOR activation. This, in turn, establishes chronic inflammation and tissue pathology in mice with important ramifications for DNA repair-deficient, progeroid syndromes and aging.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Primary Cell, Macrophage

SUBMITTER: Michalis Aivaliotis

LAB HEAD: Michalis Aivaliotis

PROVIDER: PXD015727 | Pride | 2019-11-06

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Similar Datasets

Identify the protein partners of Ercc1 in DNA damage progeria in MEFs

Project description:ERCC1 is a DNA endonuclease participating in the Nucleotide Excision Repair (NER) pathway. Its functionality is related to XPF; the two proteins work as a heterodimer to incise the 5 of a 30-mer that contains the damaged nucleotide and remove the fragment together with XPG. Apart from NER deficiency, mutated Ercc1 in mice and humans causes a series of progeroid symptoms (premature ageing). We hypothesize that there are undescribed functions of ERCC1, possibly in transcriptional regulation that contribute to the development of the striking phenotypes observed. The aim is to identify previously uncharacterized protein partners of ERCC1 that might contribute to our understanding of its differential roles during DNA damage-driven progeria.

2023-10-04 | PXD017063 | Pride

ERCC1-XPF Cooperates with CTCF and the Cohesin to Facilitate the Developmental Silencing of Imprinted Genes

Project description:Inborn defects in DNA repairare associated with complex developmental disorders whose causal mechanisms are poorly understood. Using an in vivo biotinylation tagging approach in mice, we show that the nucleotide excision repair (NER) structure-specific endonuclease ERCC1-XPF complex interacts with the insulator binding protein CTCF, the cohesin subunits SMC1A and SMC3 and with MBD2; the factors co-localize with ATRX at the promoters and control regions (ICRs) of imprinted genes during postnatal hepatic development. Loss of Ercc1or exposure to mitomycin C triggers the localization of CTCF to heterochromatin, the dissociation of the CTCF-cohesin complex and ATRXfrom promoters and ICRs,altered histone marks and the aberrant developmental expression of imprinted genes without altering DNA methylation. We propose that ERCC1-XPF cooperates with CTCF and the cohesinto facilitatet he developmental silencing of imprinted genes and that persistent DNA damage triggers chromatin changes that affect gene expression programs associated with NER disorders.

2017-04-04 | PXD005897 | Pride

miRNA array for LPS-activated tnc+/+ and tnc-/- macrophages

Project description:Endogenous molecules generated upon pathogen invasion or tissue damage serve as danger signals that activate host defence, however their precise immunological role remains unclear. Tenascin-C is an extracellular matrix glycoprotein that is specifically induced upon injury and infection. We have shown that its expression is required to generate an effective immune response to bacterial lipopolysaccharide (LPS) during experimental sepsis in vivo. Tenascin-C enables macrophage translation of pro-inflammatory cytokines upon LPS activation of toll-like receptor 4 (TLR4) and suppresses the synthesis of anti-inflammatory cytokines. It mediates post-transcriptional control of a specific subset of inflammatory mediators via induction of the microRNA miR-155. Thus tenascin-C plays a key role in regulating the inflammatory axis during pathogenic activation of TLR signaling. The data deposited here include the analysis of miRNA profile of tnc+/+ and tnc-/- bone marrow-derived macrophages (BMDMs) following stimulation with LPS for 8 hours. Bone marrow-derived macrophages (BMDMs) were cultured in complete DMEM medium, non-stimulated or stimulated for 8 hours with 100ng/ml LPS and total RNA was extracted. Samples were analysed with TaqMan Low Density Arrays (Applied Biosystems).

2012-10-18 | E-GEOD-41584 | biostudies-arrayexpress

Long Neural Genes Harbor Recurrent DNA Break Clusters in Neural Stem/Progenitor Cells

Project description:Repair of DNA double-strand breaks (DSBs) by non-homologous end-joining is critical for neural development, and brain cells frequently contain somatic genomic variations that might involve DSB intermediates. We now use an unbiased, high-throughput approach to identify genomic regions harboring recurrent DSBs in primary neural stem/progenitor cells (NSPCs). We identify 27 recurrent DSB clusters (RDCs) and, remarkably, all occur within gene bodies. Most of these NSPC RDCs were detected only upon mild, aphidicolin-induced replication stress, providing a nucleotide-resolution view of replication-associated genomic fragile sites. The vast majority of RDCs occur in long, transcribed, and late-replicating genes. Moreover, almost 90% of identified RDC-containing genes are involved in synapse function and/or neural cell adhesion, with a substantial fraction also implicated in tumor suppression and/or mental disorders. Our characterization of NSPC RDCs reveals a basis of gene fragility and suggests potential impacts of DNA breaks on neurodevelopment and neural functions. We performed high-throughput, genome-wide, translocation sequencing (HTGTS) and GRO-seq in primary mouse neural stem/progenitor cells of the indicated genotypes.

2016-02-15 | E-GEOD-74356 | biostudies-arrayexpress

A role for the Trim33 ubiquitin ligase in cellular response to replicative stress

Project description:Deregulation of RNA polymerase II (RNAPII) by oncoproteins, such as transcription factor Myc, interferes with DNA replication and is a major source of DNA damage and genomic instability. Ubiquitination is a key pathway controlling RNAPII activity via modification of RNAPII subunits or associated regulatory proteins. We uncover a mechanism for genome maintenance by ubiquitin ligase Trim33 and transcription factor E2f4. We show that Trim33 promotes E2f4 protein turnover, restricting interactions of E2f4 with chromatin and with the Recql DNA helicase. Replicative stress blunts Trim33-dependent regulation, which stimulates E2f4 and Recql recruitment to chromatin and facilitates recovery of DNA replication. Deletion of Trim33 triggers chronic recruitment of Recql to chromatin and accelerates DNA replication under stress, accompanied by compromised DDR signaling and DNA repair. Depletion of Trim33 in Myc-overexpressing cells leads to accumulation of replication-associated DNA damage and delays Myc-driven tumorigenesis. We propose that the Trim33-E2f4-Recql axis provides a mechanism to control DNA replication at transcriptionally active chromatin to maintain genome integrity.

2023-07-24 | PXD037854 | Pride

Expression data from Saccharomyces cerevisiae strains carrying the rna14-1 or the rna15-1 allele

Project description:In the yeast Saccharomyces cerevisiae, cleavage factor I (CFI) and cleavage and polyadenylation factor (CPF) build the core of the transcription termination machinery. CFI comprises the Rna14, Rna15, Pcf11, and Clp1 proteins, as well as the associated Hrp5 RNA-binding protein. We found that CFI participates in the DNA damage response and that rna14-1 shows synthetic growth defects with mutants of different repair pathways, including homologous recombination, non-homologous end joining, post replicative repair, mismatch repair, and nucleotide excision repair, implicating that impaired RNAPII termination and 3â-end processing decreases the cellular tolerance for DNA damage. Beyond replication progression defects, we found that bypass of the G1/S checkpoint in rna14-1 cells leads to synthetic sickness, accumulation of phosphorylated H2A, as well as increase in Rad52-foci and in recombination. Our data provide evidence that CFI dysfunction impairs RNAPII turnover, leading to replication hindrance and lower tolerance to exogenous DNA damage. These findings underscore the importance of coordination between transcription termination, DNA repair and replication in the maintenance of genomic stability. S. cerevisiae strains were grown in YPAD liquid culture at 30Â°C, total RNA was isolated and hybridized on Affymetrix microarrays.

2014-03-31 | E-GEOD-50947 | biostudies-arrayexpress

Transcriptional profiling of Salmonella typhimurium in the ceca of gnotobiotic mice

Project description:Transcriptional profiling of Salmonella typhimurium in the ceca of germ-free and Bacteroides thetaiotaomicron-monoassociated gnotobiotic mice. Comparison with response in MM-Glucose. In vivo transcriptional profiles of Salmonella typhimurium obtained from biological triplicate samples taken from cecal contents of germ-free and Bacteroides thetaiotaomicron-monoassociated mice 5 days post-infection with S. typhimurium. Biological duplicate samples from in vitro culture of S. typhimurium in MM-Glucose used for comparision.

2013-07-23 | E-GEOD-49076 | biostudies-arrayexpress

In vitro transcriptional profiling of Bacteroides thetaiotaomicron in lactose, galactose and human milk oligosaccharides

Project description:Investigation of the overall in vitro response of Bacteroides thetaiotaomicron to human milk oligosaccharides. Comparison with response to MM-lactose and MM-galactose (Analysis performed using as a baseline datasets GSM301635 and GSM301637 corresponding to Bacteroides thetaiotaomicron response in MM-Glucose) In vitro transcriptional profiles of Bacteroides thetaiotaomicron obtained from biological duplicate cultures taken: (i) at middle log phase in minimal media galactose (MM-Gal) and minimal media lactose (MM-L) and (ii) at two timepoints during log phase in minimal media human milk oligosaccharides (MM-HMO).

2013-01-01 | E-GEOD-26772 | biostudies-arrayexpress

Intestine-adapted bacterial symbiont response to polysaccharide rich and polysaccharide deficient diets in mice lacking fucosyltransferase-2

Project description:Analysis of Bacteroides thetaiotaomicron (BT) from the ceca of ex-germ free Fut2+ or Fut2- mice on polysaccharide rich or glucose rich polysaccharide deficient diet. BT is involved in the breakdown of plant polysaccharides and is also efficiently utilizes host glycans. BT-colonized mice represent a human gut ecosystem model. Results identify genes that may endow flexibility in adapting to dietary changes by mucosal foraging depending on host fucosylation status In vitro transcriptional profiles of Bacteroides thetaiotaomicron obtained from ceca of ex-germ free Fut2+ or Fut2- mice on polysaccharide rich or glucose rich polysaccharide deficient diet.

2014-04-21 | E-GEOD-45641 | biostudies-arrayexpress

The Quantitative Changes in the Yeast Hsp70 and Hsp90 Interactomes upon DNA Damage

Project description:The molecular chaperones Hsp70 and Hsp90 participate in many important cellular processes, including how cells respond to DNA damage. In this study, we applied quantitative affinity-purification mass spectrometry (AP-MS) proteomics to understand the protein network through which Hsp70 and Hsp90 exert their effects on the DNA damage response (DDR). We characterized the interactomes of the yeast Hsp70 isoform Ssa1 and Hsp90 isoform Hsp82 before and after exposure to methyl methanesulfonate. We identified 256 chaperone interactors, 146 of which are novel. Although the majority of chaperone interaction remained constant under DNA damage, 5 proteins (Coq5, Ast1, Cys3, Ydr210c and Rnr4) increased in interaction with Ssa1 and/or Hsp82. This data is related to article “Quantitative proteomics of the yeast Hsp70/Hsp90 interactomes during DNA damage reveals chaperone-dependent regulation of ribonucleotide reductase”.

2014-12-08 | PXD001284 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data