Date Published: January 21, 2010
Publisher: Public Library of Science
Author(s): Marinus F. van Batenburg, Hualing Li, J. Annelies Polman, Servane Lachize, Nicole A. Datson, Harmen J. Bussemaker, Onno C. Meijer, Bernadette Breant. http://doi.org/10.1371/journal.pone.0008839
Abstract: Glucocorticoids act in part via glucocortocoid receptor binding to hormone response elements (HREs), but their direct target genes in vivo are still largely unknown. We developed the criterion that genomic occurrence of paired HREs at an inter-HRE distance less than 200 bp predicts hormone responsiveness, based on synergy of multiple HREs, and HRE information from known target genes. This criterion predicts a substantial number of novel responsive genes, when applied to genomic regions 10 kb upstream of genes. Multiple-tissue in situ hybridization showed that mRNA expression of 6 out of 10 selected genes was induced in a tissue-specific manner in mice treated with a single dose of corticosterone, with the spleen being the most responsive organ. Caveolin-1 was strongly responsive in several organs, and the HRE pair in its upstream region showed increased occupancy by glucocorticoid receptor in response to corticosterone. Our approach allowed for discovery of novel tissue specific glucocorticoid target genes, which may exemplify responses underlying the permissive actions of glucocorticoids.
Partial Text: Glucocorticoid hormone secretion from the adrenal cortex follows a circadian rhythm and is markedly increased in case of physical or psychological stress, when these steroids can modulate processes in virtually all organs in the body. Glucocorticoids can act permissively to prepare for upcoming stressful challenges and support ongoing stress responses, for instance via increased gluconeogenesis and mental performance. They can also dampen the body’s initial reaction to stress, as is the case for anti-inflammatory effects. In addition, glucocorticoids can promote adaptation to stress and the response to subsequent stressors, for example by modulating memory formation. Aberrant glucocorticoid signalling is strongly linked to metabolic, immune, bone, and central nervous system disease, while important pharmacological issues include therapy resistance and side effects , , .
Detailed description of the computational procedures and the source code of all R and Perl scripts is available in supplementary Documents S1 and S2.
Through computational analysis of the spatial distribution of the GR consensus binding motif in upstream promoter regions, and its relationship with GR occupancy as measured using ChIP-chip, we have developed a simple criterion that allows for prediction of in vivo glucocorticoid responsiveness based on the 10kb sequence upstream of the transcriptional start site of each mRNA transcript annotated in the mouse genome. Testing 10 genes chosen from the list of putative targets, we identified six novel corticosterone-responsive genes. Most regulated mRNAs were found in the spleen. Caveolin-1 and two other genes showed regulation in other tissues.