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

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Item Type:Article
Title:Genome-wide analysis of LXRα activation reveals new transcriptional networks in human atherosclerotic foam cells
Creators Name:Feldmann, R. and Fischer, C. and Kodelja, V. and Behrens, S. and Haas, S. and Vingron, M. and Timmermann, B. and Geikowski, A. and Sauer, S.
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.
Keywords:Apoptosis, Atherosclerosis, Cell Line, Cholesterol, Cultured Cells, Fluorinated Hydrocarbons, Foam Cells, Gene Expression Regulation, Gene Regulatory Networks, Genetic Loci, Genetic Variation, Human Genome, Ligands, Liver X Receptors, Macrophages, Orphan Nuclear Receptors, PPAR alpha, Signal Transduction, Sulfonamides, Transcription Initiation Site
Source:Nucleic Acids Research
Publisher:Oxford University Press
Page Range:3518-3531
Date:April 2013
Official Publication:https://doi.org/10.1093/nar/gkt034
PubMed:View item in PubMed

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