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Endocrine Unit, University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK
1 Small Animal Hospital, Department of Veterinary Clinical Science and Animal Husbandry, Faculty of Veterinary Science, Crown Street, Liverpool L7 7EX, UK
2 Ludwig Institute for Cancer Research, Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA
(Requests for offprints should be addressed to Karen E Chapman; Email: Karen.Chapman{at}ed.ac.uk)
* (Alistair I Freeman and Helen L Munn contributed equally to this work) The level of expression of the glucocorticoid receptor (GR) is the principal determinant of glucocorticoid sensitivity in most cells. GR levels are permanently ‘set’ in a tissue-specific manner in response to the perinatal environment, an effect we have previously shown to relate to differential expression of tissue-enriched alternative promoters/exons 1 of the GR gene. In adult animals, GR levels are dynamically regulated around the ‘set point’ by glucocorticoids themselves, with glucocorticoids down-regulating GR mRNA in most cells and tissues. Here we have examined whether autoregulation of GR mRNA by glucocorticoids involves differential promoter regulation. We show that, in contrast to tissue-specific programming of GR mRNA levels, autoregulation of GR mRNA in vivo does not involve differential regulation of variant exon 1-containing GR mRNAs in that the major variants are down-regulated to a similar extent by glucocorticoid treatment. Consistent with this, transfections of reporter constructs showed that the majority of GR promoters, which are contained within a 4.4 kb region upstream of exon 2, are similarly regulated by glucocorticoids, with two regions of the promoter redundantly required for glucocorticoid regulation. Thus transcriptional autoregulation can occur in adult tissues around the set point established by promoter selection in early life.
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