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  Genome-wide analysis of LXRα activation reveals new transcriptional networks in human atherosclerotic foam cells

Feldmann, R., Fischer, C., Kodelja, V., Behrens, S., Haas, S., Vingron, M., et al. (2013). Genome-wide analysis of LXRα activation reveals new transcriptional networks in human atherosclerotic foam cells. Nucleic Acids Research (London), 41(6), 3518-3531. doi:10.1093/nar/gkt034.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-AA01-B Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-AA02-9
Genre: Journal Article

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 Creators:
Feldmann, Radmila1, Author              
Fischer, Cornelius1, Author              
Kodelja, Vitam2, Author              
Behrens, Sarah3, Author              
Haas, Stefan4, Author              
Vingron, Martin5, Author              
Timmermann, Bernd6, Author              
Geikowski, Anne1, Author              
Sauer, Sascha1, Author              
Affiliations:
1Nutrigenomics and Gene Regulation (Sascha Sauer), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479662              
2Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433554              
3Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433547              
4Gene Structure and Array Design (Stefan Haas), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479640              
5Gene regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479639              
6Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              

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 Abstract: Increased physiological levels of oxysterols are major risk factors for developing atherosclerosis and cardiovascular disease. Lipid-loaded macrophages, termed foam cells, are important during the early development of atherosclerotic plaques. To pursue the hypothesis that ligand-based modulation of the nuclear receptor LXRα is crucial for cell homeostasis during atherosclerotic processes, we analysed genome-wide the action of LXRα in foam cells and macrophages. By integrating chromatin immunoprecipitation-sequencing (ChIP-seq) and gene expression profile analyses, we generated a highly stringent set of 186 LXRα target genes. Treatment with the nanomolar-binding ligand T0901317 and subsequent auto-regulatory LXRα activation resulted in sequence-dependent sharpening of the genome-binding patterns of LXRα. LXRα-binding loci that correlated with differential gene expression revealed 32 novel target genes with potential beneficial effects, which in part explained the implications of disease-associated genetic variation data. These observations identified highly integrated LXRα ligand-dependent transcriptional networks, including the APOE/C1/C4/C2-gene cluster, which contribute to the reversal of cholesterol efflux and the dampening of inflammation processes in foam cells to prevent atherogenesis.

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Language(s): eng - English
 Dates: 2013-01-082013-02-072013-04-01
 Publication Status: Published in print
 Pages: -
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 Rev. Type: -
 Identifiers: DOI: 10.1093/nar/gkt034
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Title: Nucleic Acids Research (London)
  Other : Nucleic Acids Res
Source Genre: Journal
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Publ. Info: Oxford : Oxford University Press
Pages: - Volume / Issue: 41 (6) Sequence Number: - Start / End Page: 3518 - 3531 Identifier: ISSN: 0305-1048
CoNE: https://pure.mpg.de/cone/journals/resource/110992357379342