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Transcriptional control of the human glucocorticoid receptor: identification and analysis of alternative promoter regions

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Abstract

Glucocorticoid receptor levels are thought to be controlled by multiple alternative first exons. Seven of these exons are located in an upstream CpG island. In this study, we investigated the promoter activity of the intronic regions between these exons, and their susceptibility to CpG methylation and sequence variability. The seven promoters were cloned into luciferase reporter genes, and their activity measured in ten cell lines. CpG islands of 221 donors were genotyped and the effects of these SNPs were investigated in a reporter gene assay. We showed that each of the first exons was independently controlled by a unique promoter located directly upstream. Promoter activities were cell type-specific, and varied considerably between cell types. Irrespective of the cell type, in vitro methylation effectively silenced all reporter constructs. Eleven SNPs were observed within the CpG island of 221 donors, and a new promoter-specific haplotype was revealed. Four of the minor alleles reduced the reporter gene activity, with cell type specific effects. This complexity within the CpG island helps to explain the variable, tissue-specific transcriptional control of the GR, and provides insight into the mechanisms underlying tissue specific deregulation of GR levels.

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Acknowledgments

We would like to thank Hartmut Schächinger for his initiatives within the DFG-funded Trier-Leiden International Research Training Group (IRTG; GRK 1389/1) and the Institute of Psychobiology. This work was supported by the Deutsche Forschungsgemeinschaft International Research Training Group [DFG Grant GRK 1389/1]; and the Fonds Nationale de Rechearch [AFR grants TR-PHD BFR07-127].

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Authors and Affiliations

  1. Institute of Immunology, CRP-Santé/Laboratoire National de Santé, 20A rue Auguste Lumière, 1011, Luxembourg, Grand Duchy of Luxembourg

    Lei Cao-Lei, Salomon Carlos Leija, Jonathan D. Turner & Claude P. Muller

  2. Department of Immunology, Graduate School of Psychobiology, University of Trier, 54290, Trier, Germany

    Lei Cao-Lei, Jonathan D. Turner & Claude P. Muller

  3. King’s College London, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, London, UK

    Robert Kumsta

  4. Developmental Brain-Behaviour Laboratory, School of Psychology, University of Southampton, Southampton, UK

    Robert Kumsta

  5. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, J5, 68159, Mannheim, Germany

    Stefan Wüst

  6. Department of Neurobehavioral Genetics, Institute of Psychobiology, University of Trier, 54290, Trier, Germany

    Jobst Meyer

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  1. Lei Cao-Lei
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  2. Salomon Carlos Leija
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Correspondence to Claude P. Muller.

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Cao-Lei, L., Leija, S.C., Kumsta, R. et al. Transcriptional control of the human glucocorticoid receptor: identification and analysis of alternative promoter regions. Hum Genet 129, 533–543 (2011). https://doi.org/10.1007/s00439-011-0949-1

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  • DOI: https://doi.org/10.1007/s00439-011-0949-1

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