Fetal growth restriction alters transcription factor binding and epigenetic mechanisms of renal 11β-hydroxysteroid dehydrogenase type 2 in a sex-specific manner

Baserga M, Kaur R, Hale MA, Bares A, Yu X, Callaway CW, McKnight RA, Lane RH. Fetal growth restriction alters transcription factor binding and epigenetic mechanisms of renal 11 beta-hydroxysteroid dehydrogenase type 2 in a sex-specific manner. Am J Physiol Regul Integr Comp Physiol 299: R334-R342, 2010. First published April 28, 2010; doi: 10.1152/ajpregu.00122.2010.-Intrauterine growth restriction (IUGR) increases the risk of serious adult morbidities such as hypertension. In an IUGR rat model of hypertension, we reported a persistent decrease in kidney 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) mRNA and protein levels from birth through postnatal (P) day 21. This enzyme deficiency can lead to hypertension by limiting renal glucocorticoid deactivation. In the present study, we hypothesized that IUGR affects renal 11 beta-HSD2 epigenetic determinants of chromatin structure and alters key transcription factor binding to the 11 beta-HSD2 promoter in association with persistent downregulation of its mRNA expression. To test this hypothesis, we performed bilateral uterine artery ligation on embryonic day 19.5 pregnant rats and harvested kidneys at day 0 (P0) and P21. Key transcription factors that can affect 11 beta-HSD2 expression include transcriptional enhancers specificity protein 1 (SP1) and NF-kappa B p65 and transcriptional repressors early growth response factor (Egr-1) and NF-kappa B p50. Our most important findings were as follows: 1) IUGR significantly decreased SP1 and NF-kappa B (p65) binding to the 11 beta-HSD2 promoter in males, while it increased Egr-1 binding in females and NF-kappa B (p50) binding in males; 2) IUGR increased CpG methylation status, as well as modified the pattern of methylation in several CpG sites of 11 beta-HSD2 promoter at P0 also in a sex-specific manner; and 3) IUGR decreased trimethylation of H3K36 in exon 5 of 11 beta-HSD2 at P0 and P21 in both genders. We conclude that IUGR is associated with altered transcriptional repressor/activator binding in connection with increased methylation in the 11 beta-HSD2 promoter region in a sex-specific manner, possibly leading to decreased transcriptional activity. Furthermore, IUGR decreased trimethylation of H3K36 of the 11 beta-HSD2 gene in both genders, which is associated with decreased transcriptional elongation. We speculate that alterations in transcription factor binding and chromatin structure play a role in in utero reprogramming.