Nucleic Acids Research Advance Access originally published online on November 12, 2008
Nucleic Acids Research 2008 36(22):7207-7218; doi:10.1093/nar/gkn897
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Nucleic Acids Research, 2008, Vol. 36, No. 22 7207-7218
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Gene Regulation, Chromatin and Epigenetics |
Highly individual methylation patterns of alternative glucocorticoid receptor promoters suggest individualized epigenetic regulatory mechanisms
1Institute of Immunology, Laboratoire National de Santé, 20A rue Auguste Lumière, L-1011, Luxembourg and 2Department of Immunology, Graduate School of Psychobiology, University of Trier, D-54290, Germany
*To whom correspondence should be addressed. Tel: +352 490 604 220; Fax: +352 490 686; Email: claude.muller{at}lns.etat.lu
Received August 22, 2008. Revised October 22, 2008. Accepted October 23, 2008.
The transcription start sites (TSS) and promoters of many genes are located in upstream CpG islands. Methylation within such islands is known for both imprinted and oncogenes, although poorly studied for other genes, especially those with complex CpG islands containing multiple first exons and promoters. The glucocorticoid receptor (GR) CpG island contains seven alternative first exons and their promoters. Here we show for the five GR promoters activated in PBMCs that methylation patterns are highly variable between individuals. The majority of positions were methylated at levels >25% in at least one donor affecting each promoter and TSS. We also examined the evolutionarily conserved transcription factor binding sites (TFBS) using an improved in silico phylogenetic footprinting technique. The majority of these contain methylatable CpG sites, suggesting that methylation may orchestrates alternative first exon usage, silencing and controlling tissue-specific expression. The heterogeneity observed may reflect epigenetic mechanisms of GR fine tuning, programmed by early life environment and events. With 78% of evolutionarily conserved alternative first exons falling into such complex CpG islands, their internal structure and epigenetic modifications are bound to be biologically important, and may be a common transcriptional control mechanism used throughout many phyla.