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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of liver from Ercc1-/- mice and wild type littermates to investigate features of premature aging

ABSTRACT: To investigate the cause of the premature aging features in the Ercc1-/- mouse, we compared the entire transcriptome of the Ercc1-/- mouse liver to that of wildtype littermates at the age of 15 days, when the Ercc1-/- mice reached their maximal weight and had symptoms of progeria, yet overall pathology was still limited. The liver was selected because the tissue showed several well-defined histological changes associated with aging (polyploidy and intranuclear inclusions) as well as evidence that it is responding to endogenous genotoxic stress (stabilized p53).

ORGANISM(S): Mus musculus

SUBMITTER: Jan Hoeijmakers

PROVIDER: E-MEXP-834 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis.

Niedernhofer Laura J LJ Garinis George A GA Raams Anja A Lalai Astrid S AS Robinson Andria Rasile AR Appeldoorn Esther E Odijk Hanny H Oostendorp Roos R Ahmad Anwaar A van Leeuwen Wibeke W Theil Arjan F AF Vermeulen Wim W van der Horst Gijsbertus T J GT Meinecke Peter P Kleijer Wim J WJ Vijg Jan J Jaspers Nicolaas G J NG Hoeijmakers Jan H J JH

Nature 20061201 7122

XPF-ERCC1 endonuclease is required for repair of helix-distorting DNA lesions and cytotoxic DNA interstrand crosslinks. Mild mutations in XPF cause the cancer-prone syndrome xeroderma pigmentosum. A patient presented with a severe XPF mutation leading to profound crosslink sensitivity and dramatic progeroid symptoms. It is not known how unrepaired DNA damage accelerates ageing or its relevance to natural ageing. Here we show a highly significant correlation between the liver transcriptome of old ...[more]

PMID: 17183314

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Transcription profiling of liver from wild type or Ercc1 mutant mice

Project description:The XPF-ERCC1 endonuclease is required for repair of helix-distorting DNA damage and interstrand crosslinks. Here we have engineered a severe mutation in Ercc1 gene (in which the last 7 amino acids are missing; named as "Ercc1-delta") leading to extreme sensitivity to DNA crosslinks and progeria.To investigate whether a disturbance in growth and metabolism could explain the pronounced accelerated organismal deterioration seen in Ercc1 delta mice, we evaluated the liver transcriptome of 16-week-old wt and mutant mice (n=6). At this age, the Ercc1-delta mice have not yet become cachectic.

2008-06-01 | E-MEXP-1503 | biostudies-arrayexpress

Transcription profiling of liver from wild type mice of different ages to determine whether gene expression changes in naturally aged mice overlap with those from DNA repair deficient mice

Project description:To investigate whether and to which extent the gene expression changes in DNA repair deficient mice (i.e. Csbm/m/Xpa-/- and Ercc1-/-) overlap with those observed in a natural aged liver, we sought to compare the full mouse liver transcriptome of adult 16-, 96- and 130-week old wt C57Bl/6J mice (n=4) with that of adult 8-week old wt C57Bl/6J mice

2006-12-21 | E-MEXP-839 | biostudies-arrayexpress

Transcription profiling of liver from Csbm/m/Xpa-/- knockout mice to investigate the effect of nucleotide excision repair pathway inactivation

Project description:Cockayne syndrome (CS) is a photosensitive, DNA repair disorder associated with progeria caused by a defect in the transcription-coupled repair (TCR) subpathway of nucleotide excision repair (NER). Here, complete inactivation of NER in Csbm/m/Xpa-/- mutants causes a phenotype that reliably mimics the human progeroid CS syndrome. Newborn Csbm/m/Xpa-/- mice display attenuated growth, progressive neurological dysfunction, retinal degeneration, cachexia, kyphosis and die before weaning. To investigate whether a disturbance in growth and metabolism could explain the pronounced accelerated organismal deterioration seen in Csbm/m/Xpa-/- mice, we evaluated the liver transcriptome of 15-day old wt, single and double mutant mice (n=4). At this age, the Csbm/m/Xpa-/- pups have not yet become cachectic. Mouse liver transcriptome analysis and several physiological endpoints revealed systemic suppression of the GH/IGF1 somatotroph axis and oxidative metabolism, increased antioxidant responses, hypoglycemia together with hepatic glycogen and fat accumulation. Broad genome-wide parallels between Csbm/m/Xpa-/- and naturally aged mouse liver transcriptomes suggested that these changes are intrinsic to natural aging and the DNA repair-deficient mice. Importantly, wild type (wt) mice exposed to a low dose of chronic genotoxic stress and adult Csbm/m mutant mice recapitulated this response, thereby pointing to a novel link between genome instability and the age-related decline of the somatotroph axis.

2007-01-01 | E-MEXP-835 | biostudies-arrayexpress

Transcription profiling of aorta from mice underexpressing Fibulin-4 to investigate its role in elastic fibre assembly and cardio-vasuclar disease

Project description:Extracellular elastic fibres apply structure and mechanical elasticity to organs such as large arteries, lungs and skin 1. Elastic fibres are assembled through polymerization of tropoelastin monomers and loss of elastin is associated with aneurysmal degeneration of the aorta 2. The Fibulins are a six-member protein family hypothesized to function as intermolecular bridges that stabilize the organization of extracellular matrix structures such as elastic fibres and basement membranes 3. Fibulin-4 is found in the medial layers of arteries and moderately expressed in heart valves 4. To examine a potential role of Fibulin-4 in elastic fibre assembly and cardio-vascular disease we generated a mouse model underexpressing Fibulin-4. To get insight into the underlying molecular pathways involved in aneurysm formation, we determined the aorta transcriptome of Fibulin-4R/R animals and identified biological processes that were significantly overrepresented including apoptosis and cell death as well as several novel gene targets implicated in the response to aortic failure. We conclude that decreased Fibulin-4 expression causes aberrant composition of the elastin layers in the aorta and valvular leaflets, resulting in aortic aneurysms and heart abnormalities.

2007-01-01 | E-MEXP-840 | biostudies-arrayexpress

Transcription profiling of liver, lung, spleen and kidney from young (13 week) and aged (130 week) wild type mice

Project description:We compared the complete mouse liver, spleen, lung and kidney transcriptome of adult 13- and 130-wk old wt C57Bl/6J mice (n=3) to develop gene sets for young adult and aged wt mice, respectively

2008-06-01 | E-MEXP-1504 | biostudies-arrayexpress

A systems approach identifies progeroid Ercc1[-/Δ] mice as a model system for kidney aging.

2012-12-21 | GSE43061 | GEO

A systems approach identifies progeroid Ercc1[-/Δ] mice as a model system for kidney aging.

Project description:Using these samples, it has been shown that the transcriptional landscape in glomeruli of Ercc1[-/Δ] mice at a rather young age of 14 weeks mimics that of mice which have undergone real-life renal aging. Thus, young Ercc1[-/Δ] mice can be used as a model system for glomerular aging in future studies. The RNAs origin from glomerular tissues of mice of 2 distinct genotypes at 3 distinct stages of age. Between 3 and 6 replicates have been prepared per group.

2012-12-21 | E-GEOD-43061 | biostudies-arrayexpress

Down-regulation of cholesterol biosynthesis in forebrains of ERCC1-deficient mice

Project description:Background: Several genetic defects of the nucleotide excision repair (NER) pathway, including deficiency of the Excision Repair Cross-Complementing rodent repair deficiency, complementation group 1 (ERCC1), result in pre-mature aging, impaired growth, microcephaly and delayed development of the cerebellum. Such a phenotype also occurs in ERCC1-knockout mice which survive for up to 4 weeks after birth. Therefore, we analyzed cerebellar and hippocamapal transcriptomes of these animals at 3 weeks of age to identify the candidate mechanisms underlying brain consequences of reduced ERCC1 activity. Results: In the cerebellum, the most prominent change was upregulation of genes that are associated with gliosis. Although Purkinje cell degeneration has been reported in some mouse strains with NER impairment, Purkinje cell transcriptome was mostly unaffected by the ERCC1 knockout. In the hippocampus, the gliosis response was minimal. Instead, there was an extensive downregulation of genes related to lipid metabolism including several enzymes of the cholesterol biosynthesis pathway as well as lipoproteins and plasma membrane proteins. Reduced expression of the cholesterol biosynthesis pathway genes was also present in the neocortex of adult mice whose ERCC1 gene was replaced by a mutant allele with a partial activity. Conclusions: Downregulation of forebrain cholesterol biosynthesis genes is a newly identified consequence of ERCC1 deficiency. Its presence in adult mice suggests that it is not a secondary consequence of brain growth impairment. Instead, reduced cholesterol biosynthesis may contribute to such an impairment as well as affect function of mature synapses.

2011-08-16 | GSE31199 | GEO

Supplementation with Lactobacillus plantarum WCFS1 prevents Decline of Mucus Barrier in Colon of Accelerated Aging Ercc1-/Δ7 Mice

Project description:Although it is clear that probiotics improve intestinal barrier function, little is known about the effects of probiotics on the aging intestine. We investigated effects of 10-wk bacterial supplementation of Lactobacillus plantarum WCFS1, Lactobacillus casei BL23, or Bifidobacterium breve DSM20213 on gut barrier and immunity in 16-week-old accelerated aging Ercc1-/Δ7 mice, which have a median lifespan of ~20wk, and their wild-type littermates. The colonic barrier in Ercc1-/Δ7 mice was characterized by a thin (<10µm) mucus layer. L. plantarum prevented this decline in mucus integrity in Ercc1-/Δ7 mice, whereas B. breve exacerbated it. Bacterial supplementations affected the expression of immune-related genes, including Toll-like receptor 4. Regulatory T cell frequencies were increased in the mesenteric lymph nodes of L. plantarum- and L. casei-treated Ercc1-/Δ7 mice. L. plantarum- and L. casei-treated Ercc1-/Δ7 mice showed increased specific antibody production in a T cell-dependent immune response in vivo. By contrast, the effects of bacterial supplementation on wild-type control mice were negligible. Thus, supplementation with L. plantarum – but not with L. casei and B. breve – prevented the decline in the mucus barrier in Ercc1-/Δ7 mice. Our data indicate that age is an important factor influencing beneficial or detrimental effects of candidate probiotics. These findings also highlight the need for caution in translating beneficial effects of probiotics observed in young animals or humans to the elderly.

2016-10-19 | GSE87368 | GEO

Down-regulation of cholesterol biosynthesis in forebrains of ERCC1-deficient mice

2011-08-15 | E-GEOD-31199 | biostudies-arrayexpress