ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2008) 16 P671

(Lack of) Epigenetic variability in the human glucocorticoid receptor promoter CpG island

Jonathan Turner1, Laetitia Pelascini1 & Claude Muller2

1Laboratoire Nationale de Santé, Luxembourg, UK; 2Department of Psychobiology, University of Trier, Trier, Germany.

Tissue and cell type specific control of glucocorticoid receptor (GR) levels is thought to occur through the usage of alternate promoters, and associated non-coding alternate first exons. The vast majority of the known alternative first exons are located within a 3.2 kbp CpG island. Methylation of certain CpG dinucleotides within the rat Gr promoter has been implicated in changes in hippocampal GR expression levels and the resultant disturbances in the HPA axis.

Bisulphite sequencing of rat hippocampal samples has previously shown that the two CpG di-nucleotides within an NGFI-A binding within the rat exon 17 promoter (human homologue 1F) can be methylated, and that environmental changes (handling, or maternal care) induce epigenetic programming via differential methylation of the 5′ CpG di-nucleotide. Methylation of this di-nucleotide reduces NGFI-A induced promoter activity.

The available data suggests that in post mortem human brain samples there is no visible methylation of the corresponding NGFI-A CpG di-nucleotides. For both the rat and the human, the available data covers 100 bp of promoter 17/1F; however, there is no data available as to methylation patterns elsewhere within the CpG island where the majority of these alternate first exons are found.

Using readily available PBMC we performed bisulphite sequencing on promoters 1D, E, F, and H, covering approximately 45% of the complete CpG island for 26 healthy subjects (22 female and 4 male, age range 35–67, mean 51±8 years). Analysis of our data suggests that, as previously reported for human hippocampal post morten samples, the NGFI-A binding site is not methylated, and that within the context of the larger CpG island, methylation of the human GR promoter is rare. Our data suggests that epigenetic mechanisms do not play a role control of human GR transcription.

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