The data reported here are consistent with previous reports of alterations in cytosine methylation associated with psychopathology35–37. We found increased site-specific methylation of the exon 1F NR3C1 promoter in suicide victims with a history of childhood abuse (Fig. 2). Our transfection studies with constructs that replicated the in vivo methylation profiles indicated that there was a relationship between cytosine methylation, transcription factor binding and gene expression. Variations in maternal care in the rat produce differential methylation of the exon 17 Nr3c1 promoter, the rat homolog of the exon 1F NR3C1 promoter, which regulates hippocampal glucocorticoid receptor expression4,17,22 and HPA responses to stress3,4. Increased CpG methylation of the Nr3c1 promoter decreased NGFI-A binding and reduced hippocampal glucocorticoid receptor expression. Manipulations that reversed the differences in exon 17 methylation eliminated the maternal effect on NGFI-A binding, glucocorticoid receptor expression and HPA activity4,22. Likewise, our in vitro data reveal that differential methylation of the human NR3C1 promoter altered NGFI-A binding and NGFI-A–induced gene transcription. These findings suggest that selective differences in methylation status at certain sites affect transcription factor binding and gene expression.
