Unknown,Transcriptomics,Genomics,Proteomics

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Regulatory interplay of Cockayne syndrome B ATPase and stress-response gene ATF3 following genotoxic stress

ABSTRACT: Gene expression profile in CS1AN deficient and CSBwt restored cell lines after 24 hours of UV or alphe-amanitin treatment (only for restored). The comaprison of expression profile between 0 and 24 hours revealed continouse suppresion of transcription upon UV treatment in CS1AN cell line and alpha-amanitin treated CS1AN CSBwt restored cells. Gene expression profiles were obtained in duplicates for un-treated (assigned as 0h time point) and treated (assigned as 24h time point) cells.

ORGANISM(S): Homo sapiens

SUBMITTER: Egly Jean-Marc

PROVIDER: E-GEOD-57923 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Regulatory interplay of Cockayne syndrome B ATPase and stress-response gene ATF3 following genotoxic stress.

Kristensen Ulrik U Epanchintsev Alexey A Rauschendorf Marc-Alexander MA Laugel Vincent V Stevnsner Tinna T Bohr Vilhelm A VA Coin Frédéric F Egly Jean-Marc JM

Proceedings of the National Academy of Sciences of the United States of America 20130603 25

Cockayne syndrome type B ATPase (CSB) belongs to the SwItch/Sucrose nonfermentable family. Its mutations are linked to Cockayne syndrome phenotypes and classically are thought to be caused by defects in transcription-coupled repair, a subtype of DNA repair. Here we show that after UV-C irradiation, immediate early genes such as activating transcription factor 3 (ATF3) are overexpressed. Although the ATF3 target genes, including dihydrofolate reductase (DHFR), were unable to recover RNA synthesis ...[more]

PMID: 23733932

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Project description:Background & Aims: Overnutrition is one of the major causes of non-alcoholic fatty liver disease (NAFLD) and its advanced form non-alcoholic steatohepatitis (NASH). Besides the quantity of consumed calories, distinct dietary components are increasingly recognized as important contributor to the pathogenesis of NASH. We aimed to develop and characterize a hitherto missing murine model which resembles both the pathology and nutritional situation of NASH-patients in Western societies. Methods: We developed a NASH-inducing diet (ND) enriched with sucrose, cholesterol and a high concentration of fats rich in saturated fatty acids in a composition which mimics Western food. C57Bl6/N mice were fed with the ND or control chow for 12 weeks. Biochemical, real-time polymerase chain reaction, Western Blot and immunohistochemical analyses were performed to characterize systemic and hepatic changes induced by ND-feeding. Immunohistochemistry was used to assess c-Jun levels and activation in 110 human NAFLD and control liver specimens applying tissue micro array technology. Results: ND-fed mice showed significant body weight gain, impaired glucose tolerance, elevated fasting blood glucose levels as well as decreased adiponectin and increased leptin serum levels compared to control mice. In the liver, ND-feeding led to marked steatosis, enhanced cholesterol levels, distinct signs of oxidative stress, hepatocellular damage, inflammation, activation of hepatic stellate cells, and beginning fibrosis. Transcriptome-wide hepatic gene expression analysis comparing ND-fed mice and control mice indicated main alterations in lipid metabolism and inflammatory processes. Search for over-represented transcription factor target sites among the differentially expressed genes identified AP-1 as the most likely factor to cause the transcriptional changes in ND-livers. Combining differentially expressed gene and protein-protein interaction network analysis identified c-Jun (a component of the AP-1 complex) as hub in the largest connected deregulated sub-network in ND-livers. In accordance, ND-livers revealed c-Jun-phosphorylation and nuclear translocation. Moreover, hepatic c-Jun RNA and protein expression was enhanced in ND-fed compared to control mice. Also NAFLD-patients showed enhanced hepatic c-Jun levels, which correlated with inflammation, and notably, with the degree of hepatic steatosis. Conclusions: The new dietary mouse-model shows important pathological changes also found in human NASH and indicates c-jun/AP-1 activation as critical regulator of hepatic alterations. Abundance of c-jun in NAFLD likely facilitates development and progression of NASH, and thus, c-jun appears as attractive prognostic and therapeutic target of NAFLD progression. 14-weeks old male C57BL/6N mice were fed with either regular diet or a newly designed NASH-inducing diet for 12 weeks. Hepatic gene expression levels were measured thereafter.

Dataset Information

Regulatory interplay of Cockayne syndrome B ATPase and stress-response gene ATF3 following genotoxic stress

Publications

Regulatory interplay of Cockayne syndrome B ATPase and stress-response gene ATF3 following genotoxic stress.

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